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Editor's Note: From the American Heart Association Scientific Sessions in Orlando FL, Dr Fuster and panel discuss a single risk-factor-modification strategy in SPRINT, early intervention with ambulatory troponin tests in PROACT-4, late surgical intervention in severe ischemic mitral regurgitation, and primordial prevention using peer support in the Fifty-Fifty trial. The runner-up trials for consideration are nitrates in HFpEF, the use of IVUS to improve the outcomes of stenting long lesions, RIVER-PCI on ranolazine after PCI, and the PRADA trial on prevention of cardiac dysfunction during chemotherapy.
Introduction
Dr Valentin Fuster: I am Valentin Fuster from New York. It is a pleasure to be surrounded here by my panelists, who are all stars. How I'm going to control them may be a problem.
Starting on my right, Dr Carl Pepine, professor of medicine and chief of the division of cardiovascular medicine at the University of Florida School of Medicine in Gainesville.
Professor Vera Bittner, professor of medicine, section head of preventive cardiology at the University of Alabama in Birmingham.
Then we have Dr Pat O'Gara, past president of the American College of Cardiology, professor of medicine at Harvard Medical School, and senior physician of cardiovascular medicine at the division at Brigham and Women's Hospital in Boston.
And Dr Clyde Yancy, who is a veteran of the Cardiology Show. He is Magerstadt professor of medicine, professor of medical social sciences, and chief of the division of cardiology at Northwestern University Feinberg School of Medicine. Clyde, again, thank you.
Dr Anne Curtis, who has been here three or four times before. And she's a distinguished professor, Charles and Mary Bauer professor and chair, department of medicine at the University of Buffalo School of Medicine and Biomedical Sciences in New York.
We have interesting subjects to discuss. The topics that we are going to discuss in more detail are first, the SPRINT trial. It's part of the theme of single risk factors with an impact, blood pressure.
The second will be on early intervention. This is the PROACT-4 study on checking troponins in the ambulance to gain time.
The third one concerning later intervention is on mitral regurgitation. What kind of intervention do you do with severe mitral regurgitation when it is ischemic in origin, which is quite different from mitral-valve prolapse.
And the fourth theme is primordial prevention—that is, promoting health and preventing disease. And this is the Fifty-Fifty trial, which is based on group therapy.
SPRINT: Systolic Blood-Pressure Intervention Trial
Dr Fuster: Let's begin with the trial that everybody's talking about. Are they talking about it because it's clear or because we are confused? Let's see.
When I was a medical student an acceptable blood pressure was 160 mm Hg systolic. Then it went to 120 mm Hg, then 130 mm Hg, and recently we were told that 140 mm Hg was okay from age 60 [Editor's Note: The JNC8 blood-pressure guidelines for adults suggest a goal of 150/90 mm Hg in patients over age 60 and 140/90 for everybody else].
Now, SPRINT says less than 120 mm Hg.
If you single out one factor, then hypertension is the number-one killer in the world. According to most of the studies, in terms of stroke, myocardial infarction, and renal disease, the systolic blood pressure is more important than diastolic hypertension.
There has been a lot of uncertainty about the target level for blood pressure. I have my own bias. I think the patients in each study are different, and it depends on who are you talking about. In addition, who is checking the blood pressure, and what mechanism is being used to check the blood pressure? We will discuss this in a moment.
In 2007, the [National Institutes of Health] NIH [National Heart, Lung, and Blood Institute] NHLBI decided to investigate whether we should be more aggressive in trying to drop the systolic blood pressure to less than 120 mm Hg. This led to the SPRINT research group, which presented their findings at this meeting,[1] and they published them in the New England Journal of Medicine.[2] The SPRINT trial was a randomized trial of intensive vs standard blood-pressure control presented by Dr Paul Whelton from Tulane University (New Orleans, LA), who was the chair of the steering committee.
There were nearly 10,000 patients with SBP of ≥130 mm Hg who were at least 50 years of age and at increased cardiovascular risk; however, patients with diabetes and any prior stroke were excluded. They had to have one of these four risk factors: ≥75 years, subclinical or clinically evidence cardiovascular disease, renal disease with glomerular filtration between 20 and 60 mL/min/1.73m2, or a Framingham risk of ≥15% at 10 years.
The aim was to reach a blood pressure of <120 mm Hg in the intensive-treatment group or a target of <140 mm Hg in the so-called standard-treatment group. The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.
At 1 year of follow-up, the mean SBP was 121 mm Hg in the intensive-treated group (not bad) and 136 mm Hg in the standard-treatment group. And now came the surprise. The study was stopped at about 3 years of follow-up (2 years before it was supposed to finish).
The intensive-treatment group had an event rate of 1.65% per year and in the standard-treatment group it was 2.19% per year. It doesn't shake you up. If you look at relative risk, you can call this a 25% decrease. But the numbers we are dealing with are very small.
All-cause mortality was also significantly lower in the intensive-treatment group. But we have an issue. The rates of serious adverse events—hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure—were 4.7% in the aggressively-treated group, but 2.5% in the standard-treatment group.
The paper's conclusion is that among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of <120 mm Hg compared with <140 mm Hg resulted in lower rates of fatal and nonfatal cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group.
I'm going to ask the same question to each of you, and you give me an answer in no more than 15 seconds. Will you change your practice after this study? Carl?
Dr Carl J Pepine: Yes.
Dr Fuster: In what way?
Dr Pepine: Well, I've always been an advocate of intense treatment of blood pressure but not as low as those goals, particularly in elderly people. Now, I will continue to use multiple medications to lower the blood pressure in and about those goals, when in the past I had been withdrawing medications in my elderly patients.
Dr Fuster: Vera?
Dr Bittner: I also feel a little better about treating older patients more intensively, in contrast to what was recently recommended, where the blood-pressure goals had actually become more lenient. And there are a lot of people with blood pressure that is out of control at this point.
Dr Fuster: Pat?
Dr O'Gara: I think it'll have to be individualized. I can imagine having a lot of conversations with patients to the effect that they're already taking two medications, and they're not really interested in taking a third, and going back through other lifestyle changes that they might be able to make to improve their blood-pressure profile. Now, how this plays out in clinical practice remains to be seen.
Dr Fuster: Clyde?
Dr Yancy: It will change my practice in selected patients. I'm really curious about the findings that part of the benefit is a reduction in heart-failure events. We need to understand that a bit better. But if that really is verifiable, I think that gives us a brand-new opportunity to change the natural history of a disease that I deal with every day. So in selected high-risk patients, I will target that lower number.
Dr Fuster: Thank you. Anne?
Dr Anne B Curtis: Based on the results of the study, there's every reason to treat patients to get the blood pressure to a lower goal. The thing to remember is that the patient's had cardiovascular risk factors or overt cardiovascular disease. It's very easy to extend this to everybody, to start thinking that it's a blanket recommendation, but as everybody here has been saying, you've got to individualize it. I would also hypothesize that if you treated these patients who were in better health now over a longer period of time, there will also be benefit.
Dr Fuster: I have a problem that I'd like you to answer. My problem is when you look at the number of people who really belong to this study, it's no more than 25% of the hypertensive population. They don't have diabetes (which is 30% of the usual hypertensive population). They don't have previous stroke. Most of the patients in the study are in their 70s, none are under age 50. The event rates of syncope, hypotension, and so forth are very significant. I am very cautious because this is not necessarily the overall population we see with hypertension.
Carl, I know you are going to change your practice, but how do you respond to my comments?
Dr Pepine: First of all, the SPRINT trial was done on the background of ACCORD,[3] which thought it answered the questions in patients with diabetes. ACCORD showed a significant reduction in stroke, but the investigators chose to say that, considering the problems with medications and so forth, it's probably not worthwhile.
There was a significant reduction in stroke in SPRINT and in heart failure, as Clyde has noted [Editor's Note: The reduction in stroke did not reach statistical significance]. Both of those are extraordinarily important. To your point about hypotension, actually symptomatic (orthostatic) hypotension was not different between the two arms.
Dr Fuster: Syncope and hypotension were higher [with intensive treatment].
Dr Pepine: Syncope was, but what they described as hypotension with dizziness wasn't, which is what we all see in the older population. [Editor's Note: hypotension was higher in the intensive group, but orthostatic hypotension was higher in the standard-treatment group].
The other outcome which you skipped over was injuries. Fall with injury was not different between the groups. I'm not so concerned anymore about the cautions that the ACCORD investigators made.
Another point is that although they excluded diabetes, the fasting blood sugars were a mean 99 mg/dL. These were clearly prediabetic patients. We all know that the 126-mg/dL cutoff for diabetes is a very artificial one, and the relationship between adverse outcomes and blood sugar starts at about the mid-80s. I think you can make implications about the diabetic population from this trial.
Dr Fuster: Pat, how many patients whom you see who are age 70 and 80 are you going to treat to less than 120 mm Hg?
Dr O'Gara: I think it would be problematic. And to get back to some of your introductory comments, I have to express the same degree of confusion. First, it's fair for us to recognize the results were a surprise. Second, the ACCORD trial didn't meet its primary end point. We also had information about treating patients with chronic kidney disease to the contrary, about the potential hazards of intensive therapy vs routine therapy for blood-pressure control. So I'm a little bit on the sidelines about this. I'd like to see further commentary, further discourse.
The big question is, to what extent does a single trial impact guideline development and recommendations made at an organizational level? What is the process and the timeline over which that should be done? I think it's very complicated, because we've seen very attractive trials in other areas of cardiovascular medicine and intervention. Then we take a step back and there's some modulation on the initial enthusiasm. I'm not saying that the hypothesis is incorrect, especially with population studies saying that 110 mm Hg is really a good blood-pressure target. But how this shakes out in real practice remains to be seen.
Dr Fuster: I have a question for Clyde and Anne about the statistics. One of the critical issues is, what is the P value, and the other thing is, what is the impact? Let me read you the number of events again: 1.65% per year in the aggressively treated group and 2.19% per year in the standard-treatment group. You can call that a 25% relative risk reduction, but it's a quite different absolute risk reduction. And this bothers me because the rate of serious adverse events is 4.7% vs 2.5%, but there's no comment in the paper on the relative decrease. Those numbers are just left as is. How we read papers is critically important. I'd like you to comment, Clyde.
Dr Yancy: It's how we read the paper, but I also think it's going to be how we implement the data, because when you understand that the SPRINT-like population of hypertensives in this country may be about 10 million people, then that 25% risk reduction, even with small, absolute risk reductions, captures quite a number of events. There's no condition that we treat that doesn't come with some attendant side effects from the therapies.
When I particularly like about the conversation that you and Pat were having, though, is that I'm actually pleased that we can partition out some of the hypertension. It always concerned me that it's just about the numbers. Get the numbers down. It has to be more individualized than that. And now, at least we know if you've got a risk burden and are hypertensive, we can guide your therapy more precisely than before. But it doesn't answer all questions about hypertension. But I am comfortable with the statistics.
Dr Fuster: Anne, give us a course on statistics.
Dr Curtis: Well, I don't think I could do that. But beyond the actual numbers that Clyde was talking about, you mentioned rates per year. Well, if you look over a long period of time, 10, 20, years, now, those are going to add up.
Dr Fuster: Well, we're not sure. We need the data . . .
Dr Curtis: That is true. But I don't see any reason to think that's not true, either. The other point you mentioned at the beginning is how we define hypertension. Is it 130, 140, 120 mm Hg? If I've got a patient who's sitting at 130 mm Hg, and I can easily get that down a little bit more, why not? I don't think there's any downside to that. And so that should be a target. Do I want somebody walking around who's dizzy because I've hit them with so many meds? That would be the wrong message to take from this.
Dr Fuster: Okay, what I heard is a trend for all of you to change your practice. Pat O'Gara and I are a little bit cautious.
I think it's an excellent study in terms of how it was carried out (methodologically speaking). But my main concern is that we see so many people with hypertension who are excluded from this group. And perhaps, we have to be cautious.
PROACT-4: Point-of-Care Troponin Testing
Dr Fuster: Let's now move into early intervention. We are talking about troponins. Everybody talks troponins these days.
The question is if measuring troponins in the ambulance in patients with chest pain will gain you some time, which could be beneficial. This study is called PROACT-4, for Providing Rapid Out-of-Hospital Acute Cardiovascular Treatment. It's from Paul Armstrong's group in Canada, and the presenter was Dr Justin Ezekowitz (University of Alberta, Edmonton).
We all know that when patients with chest pain come to the emergency room, most of the time, the chest pain is not coronary in origin. Most of them come via ambulance. The question is, can we gain time when the patient is in the ambulance in case this is a myocardial infarction?
Can a high-sensitivity troponin test in the ambulance facilitate a shorter time from the first medical contact to the final disposition of the patient in the emergency department? There are two implications. One is clinical and the other, I suspect, is economical.
The secondary end point was a reduction in 30-day clinical events. The trial included 600 patients who had chest pain presenting in the emergency rooms. Half of them already had their troponin drawn (results take between 15 and 18 minutes). This laboratory was set up in 25 of the ambulance systems in the Edmonton area of Canada.
Before we discuss the results, it's interesting that the first troponin [test result] was available within 38 minutes after the patient had their blood drawn for the group that was tested in the ambulance. For those who were tested in the hospital, the time from the first encounter with a doctor to the troponin result was 138 minutes. So you gain about 100 minutes.
How many patients had high troponin? It was 14% of the group tested in the ambulance and 9.5% of the group tested in the hospital.
The results were disappointing. From the first medical contact to the final disposition was practically the same, 9 hours 14 minutes in the usual-care group and 8 hours 85 minutes in the group in which troponins were drawn in the ambulance, not much difference [Editor's Note it was 9.14 hours (ie, 9 hours and 8 minutes in the usual-care group) and 8.85 hours (ie, 8 hours and 51 minutes in the point-of-care test group)].
In terms of the secondary end point, the number of events was very small and was the same in both groups. The conclusion is that the results were somewhat negative, but they say we should carry on, and maybe we will distinguish low-risk and high-risk population and expedite patients more rapidly.
That's fine, but it didn't work the way it was presented. I just recently reviewed the time from chest-pain onset to the time the patient calls the ambulance. That period is long. That to me, is the crux of the problem here.
Dr Curtis: The results of the study itself are pretty underwhelming, why anybody thought that an hour's worth of difference getting to the emergency department would affect outcomes a month later. I'm not that surprised about that.
In terms of awareness at home, you're absolutely right. It's people recognizing symptoms, and people don't want to think they're having cardiac problems, so they want to blame it on indigestion or anything else. We still need a massive public-education campaign.
Dr Fuster: Do you think it's because they don't feel vulnerable, and that's why they think the stomach is the problem? Or do you think it's also a sense of embarrassment about showing up in an emergency room with nothing? When you ask patients, they say well, I didn't want to bother the doctor.
Dr O'Gara: I think you're right. And there are cultural issues. There are gender issues. There are age-related issues that people don't activate 911, misinterpreting the importance of their symptoms. That is public-enemy number one. And when it comes to reducing the time between onset of symptoms and reperfusion, I think this study was disappointing because it perhaps missed the mark.
If there is this discrepancy between having information available almost 2 hours earlier, but no effect on the time between knowledge and disposition, what's happening in the interim that continues to delay people getting to the appropriate disposition out of the emergency room? We still have the same ingrained protocols; for example, the second troponin needs to be drawn, and on and on. This is a low-risk population, and they attempted to define what's low risk and what's very low risk, but it's the processes in between that seem to be at issue here.
Dr Fuster: Vera, you are involved in promoting health and education. Do you think that we should educate people? Of the six of us, I'm sure none of us ever thought that a patient coming to us with chest pain should be embarrassed if it's nothing. The question is, could we educate people to just go to the hospital, regardless? Do you think this is possible? Because this is the time that is most precious that we are really wasting at this moment.
Dr Bittner: I was part of the REACT study[4] [Rapid Early Action for Coronary Treatment] many years ago, which was a community-based intervention study where communities were randomized to getting educational materials about getting to the emergency room quickly and then compared with control communities to make sure that there was no secular effect there.
And what basically came out of this trial is that you can raise awareness that knowledge actually improves, but behavior doesn't necessarily change. The time to arrival in the emergency room didn't change. And more disappointingly, once interventions stopped, there was attrition of the awareness as well. I'm not so sure that education is necessarily will work.
Dr Fuster: It's a very good point. We know many things, but we behave differently when we know. And this is really the issue of risk-factor profile problems.
It was an interesting study, but certainly, we have a challenge here.
Dr Pepine: Actually, Vera, if I'm not mistaken, in that REACT trial, the control communities that didn't get the education actually had a greater improvement.
Dr Bittner: The problem was that it was diluted because there were simultaneous nationwide campaigns, and it was a hard to sort out how much information they actually got.
Mitral Valve Repair or Replacement for Severe Ischemic MR
Dr Fuster: We moved from a single risk factor, blood pressure, to early intervention, and now we come to an intervention at a more chronic state. I would like to discuss mitral regurgitation [MR].
There have been significant advances in terms of mitral-valve repair in mitral regurgitation. But most of the time, we are talking about degenerative mitral regurgitation. There are fewer data on ischemic mitral regurgitation, which when it is significant is very important in terms of mortality. In fact, the mortality rates are 15% to 40% at 1 year for severe ischemic mitral regurgitation.[5,6]
The study that we are talking about is a study that has been sponsored by the Cardiothoracic Surgical Trials Network.[7] Were you the head of this group, Pat?
Dr O'Gara: Cochair.
Dr Fuster: Well, you know this study very well. It has been going on for 2 years and is titled "Two-year outcomes of surgical treatment of severe mitral regurgitation." And the paper was presented by Dr Daniel Goldstein from the Einstein School of Medicine in New York.
If you have a patient with ischemic heart disease and the patient has significant mitral regurgitation, I don't think there is much debate that this patient should have an intervention. And if you can intervene at the coronary arteries at the same time, this is basically what we all do.
But the question is, what kind of mitral-valve intervention should we do? We have two approaches—replace or repair. This study took 250 people across the country and tested putting a narrower ring in restricting the mitral valve vs a conservative approach sparing the chordae tendineae and papillary muscle and then putting in a bioprosthetic valve, because as we know, you can get low cardiac-output syndrome, if you don't have the chordae tendineae.
This was basically the study. Pat, how many patients who had valve replacement got a bioprosthetic valve vs a mechanical valve?
Dr O'Gara: Essentially all of them had a bioprosthetic valve.
Dr Fuster: That's what I assumed, although they were different ages.
Dr O'Gara: Yes
Dr Fuster: We are talking about 251 patients with significant mitral regurgitation secondary to ischemic heart disease. The patients had clinical and echocardiographic outcomes, and we discussed the 1-year results last year [Editor's Note: the 1-year results were presented at AHA 2013 and discussed here ]. The 1-year findings are published in the New England Journal of Medicine[8]—the end systolic volume index was not different between the groups at 1 year, nor was survivorship or adverse events. So the results were very equal, although there was some degree of mitral regurgitation in the group that received repair that required follow-up. The 2-year follow-up is really striking, bad news.
Mortality rates are practically the same: 19% in the repair group and 23% in the replacement group. The problem is that moderate to severe mitral-regurgitation rates were 58% of the repair group and 3.8% in the replacement group. These patients then go into heart failure, and they have more hospital admissions, which was a secondary end point.
This randomized study of ischemic heart disease with significant mitral regurgitation clearly shows that recurrence of mitral regurgitation is a significant problem in the repair group. When this happens, it tends to be progressive. Pat, since you were part of this study, do you think that some surgeons are better than others? Do you think that people who have great experience in repair are going to repair the problem?
Dr O'Gara: Well, that's a really good question, and I can't wait for Clyde to answer it. He was a member of the [data safety and monitoring board] DSMB for this trial.
Dr Fuster: At least he didn't stop this trial.
Dr O'Gara: No, he didn't stop it. There has been a criticism from surgical quarters that perhaps we didn't know how to repair these valves. And as you point out, this is a very different disease from myxomatous disease, and repair is simply a downsized annuloplasty procedure. Very few of these repairs were accompanied by subvalvular procedures (only 12%).
And the interesting thing is that fewer than 3% of patients left the operating room with moderate or greater mitral regurgitation. So 97% of patients had an adequate repair as visualized on transesophageal echocardiography at time of surgery. And the vast majority of recurrent MR occurs in the first 30 to 60 days after the procedure.
The problem that we face as clinicians and certainly from our surgical colleagues' perspective is, can you predict who would do well with a repair compared with a replacement? We have a companion investigation that was published in a different journal[9] that looked at 35 variables to try to find predictors of a bad repair right from the get-go—it's posterobasal aneurysm. But we couldn't recapitulate many of the other echocardiographic and clinical variables that had been identified in observational, single-center studies without an echo core lab. So we've tried to look at this assiduously.
Dr Fuster: Clyde, one of the problems—we know a lot about prolapsed valves, but we know very little about this, anatomically and functionally. Is that correct?
Dr Yancy: Not only is that correct, but it recognizes that we have to appreciate the burden of MR on ventricular performance. We're talking about 20% of these patients that succumbed over the 2-year period of time. And we can't believe that this MR isn't clinically important. It is especially since it's of ischemic etiology. It does merit the attention that the network paid to it because it does predispose to LV dysfunction and heart failure.
Dr Fuster: Carl, do you have any comments to add?
Dr Pepine: We don't really make this decision as cardiologists. We make a decision that the patient ought to have something done. But in general, the choice of the procedure is in the surgeon's hands. I'm a little bit on the side—as Pat mentioned—a lot of this might have to do with the expertise in repair in the hands of the surgeon. I would still feel very comfortable with a surgeon who has that expertise.
Dr Yancy: Val, if I can contribute something else here, I think it's really important to appreciate what was done in this trial. This was a randomized trial. So unlike many of the other experiences, these data are protected by the power of randomization. You really are testing a single hypothesis. Yes, skill may vary somewhat. But I think the power of randomization equalizes that.
Most of the signals and the conversations prior to this trial were based on smaller surveys, smaller experiences that didn't have really well-configured control populations. I do think these are very relevant data. I agree with you, Carl, that we don't get a chance to make this decision. But I'm concerned that sometimes, the decision is not made on the basis of evidence.
Dr Fuster: It's interesting, because it depends where the infarct is. There are so many variables here. If you replace the valve (by whatever mechanism), you need to know what you are doing when repairing a valve with infarct, it can be in any part of the wall, and any disturbance of the papillary muscle may be a problem.
Any comments, Anne?
Dr Curtis: I was impressed by the fact that so many of the repairs looked like they were good at the end of the operation. If that were the case, then 58% of patients should not have moderate to severe MR afterward. That does not speak well for the repair.
Dr O'Gara: These patients were cared for in major academic surgical centers across the United States and from colleagues who would be considered good mitral surgeons.
One of the other take-home messages about this disease vs myxomatous disease and what the average person would think about a ventricle in somebody with severe ischemic mitral regurgitation is that these patients had ejection fractions of 40%, not 20%, going into the trial. And as well as they were cared for, the 2-year death rates were 20%—this is a lethal disease. We're too far down the road in trying to affect the natural history in a significant way.
Fifty-Fifty: Peer-Group Intervention in Risk-Factor Modification
Dr Fuster: Good point. Let's move now into something that the American Heart Association and Google and everybody is talking about, and that's prevention. According to what I read in the past few days, it's over; we will not have disease anymore. We'll have to close the shop.
There are two papers that were presented on primordial prevention. One was mine[10,11]—I apologize for including it, but I feel so excited about it. This is concept that we developed similar to Alcoholics Anonymous. I work as a volunteer for Alcoholics Anonymous, and I realize the power of group therapy.
We did two pilot studies. One was in the small town, Cardona, where my wife is from in the north of Spain. The other was in the island of Granada in the Caribbean, because we wanted a heterogeneous group. We realized that group therapy can work anywhere in any type of socioeconomic status.
The government of Spain encouraged me to develop a study of group therapy in seven communities in the country. We went to the town hall of seven communities, and we asked for volunteers to be part of an educational program that lasted about 10 hours. We taught them the four risk factors that are not laboratory-oriented, to make things simple. We called this BEWAT for blood pressure, exercise, weight, alimentation, and tobacco. Additional major risk factors per the AHA are cholesterol and blood sugar.
Then we added two more: one is how to motivate people, and the other is how to control stress, because what we found is most of these people with these risk factors are under significant stress.
About 1500 people showed up. We selected those who had at least one of the risk factors, leaving over 500 people.
After we did the teaching, we did the randomization. Everybody had 10 hours of training. We took 250 and put them in groups of 10 participating in monthly group therapy. They talked for about 1 to 2 hours, helping each other over the period of 1 year. So they met 12 times.
The other 250 just had the education. We followed both groups for a period of a year. And at the end of the year, through questionnaires, validating with the families—we tabulated how they did in terms of a scoring system. The scoring system is very simple and uses the five risk factors scored 0 to 3. For example, if your blood pressure is perfect, it's a 3. If your blood pressure is very high, it's a 0.
On average, most people had just one single risk factor. So when you do averages, one point is a lot. It was very significant in favor of the group therapy. And what was fascinating is that the scores for both groups went up after the educational program. But the group that didn't have the group therapy, their scores returned to the same level that they started, and the other continued to go up.
Basically, group therapy is very motivating. They really got very engaged. In January of this coming year, we'll have 1-year of follow-up of all these individuals to see if this is actually sustainable.
Dr Bittner: I was obviously excited to see that that worked. It's not so dissimilar to what we see in cardiac rehabilitation a lot of times, in that part of the benefit in rehab is the patients interacting with each other. A good number of them become friends sometimes from very disparate backgrounds, and then afterward they exercise together at gyms. They stay in contact. They go to lunch with each other. I think having that social support network is a very important part of being able to stick to these behavior modifications, because at home, your usual environment at work or in the family, things may not necessarily change.
Dr Fuster: It's interesting, Anne. One of the things we found was that the group leader had to have a significant weakness (the people choose their leader). When the leader is very obese or smokes two packs a day but is very motivated, it's a tremendous asset. Once these people see somebody leading who has a significant weakness, it's curious how humans are.
Dr Curtis: It means that they're more willing to follow them. What I love about the study is that this is actually pretty cheap in terms of healthcare costs. If you can make an impact on people in that kind of a group situation, if the obesity goes down, the blood pressure goes down, there are a lot of other savings to be had.
Dr Fuster: We now have a study at Harvard sponsored by the American Heart Association with 1000 families. The original work we did was with children between age 3 and 6, now this is with the parents (age 20 to 30) and we are working now on families to see whether we can have an impact. Any comments, Pat?
Dr O'Gara: It's spectacular. As Anne was saying, it's a wonderful intervention that doesn't seem to cost anything. If we can expand this to other communities, get churches involved, and people where they live and how they interact with each other. It's a terrific example of this peer group approach to which you refer, Alcoholics Anonymous.
Dr Pepine: In other studies, we would call this peer pressure. It's disappointing that most of the schools have taken health programs out of their curriculum. And that's where they would get this education, but that's gone.
Dr Fuster: Clyde, any comments?
Dr Yancy: First of all, you should be congratulated. This is a terrific example of what is emerging as the next area of research, using patient engagement and patient-centeredness, where patients actually own some of this. Now, they aren't patients just yet, more citizens and people. When there's an investment, and it's no longer a one-way dialogue between the care provider and the person, but a two-way dialogue, and they're educating each other, the opportunity for traction with the messages that are being delivered is much better than if it's one of us speaking with someone directly.
Dr Fuster: The NHLBI decided just a few months ago to invest in health as a priority, but what is health? It's a very interesting change in mode from the clinical, from the molecular level; at all levels, it's better we begin to understand what health is about. Before we know all these—that you see.
Dr Pepine: Could you tell us what instruments you used in these peer groups to help motivate people? Did you use social networking? Did you have any Internet-based or phone-based cues and things?
Dr Fuster: Part of the education was through the Internet. We had many tools that were developed by a number of psychologists. We did have a great investment in terms of infrastructure. The end result is economical, but the development of that with at least 100 people involved took a couple of years. Now we are measuring everything.
NEAT-HFpEF: Nitrates and Activity in Preserved EF HF
Dr Fuster: Now, we are going to the backup studies, right? The first one is interesting: It's on HF with preserved ejection fraction. I picked this because 95% of the patients had hypertension, so it fits with the first trial (SPRINT). This is called NEAT-HFpEF.[12]The N is for nitrates. This was simultaneously published in the New England Journal of Medicine[13] as "Isosorbide mononitrate in heart failure with preserved ejection fraction." Dr Margaret Redfield from the Mayo Clinic, on behalf of the NHLBI Heart Failure Clinical Research Network, presented this study.
How many people do we see with hypertension and obesity, etc, who end up with this kind of cardiac failure, which is somewhat complex? Many of them have pulmonary hypertension, so to use isosorbide made sense. It certainly works when the ejection fraction is low. I thought it was quite interesting to test it. I must admit that I have used it in a number of patients—now I see this was wrong.
Dr Bittner: We're all in the same boat.
Dr Fuster: This study results were the complete opposite of the hypothesis. There were 110 patients in a multicenter, double-blind study with heart failure and preserved ejection fraction who were randomized to isosorbide once daily or placebo [Editor's Note: the dose was uptitrated from 30 mg to 60 mg to 120 mg of study drug and continued on 120 mg or the maximally tolerated dose].
Then there was a crossover period of 6 weeks. The primary end point was daily activity level, measured as daily accelerometer units during the 120-mg phase. The secondary end point was the same [meaning additional accelerometer measures] and 6-minute-walk distance, quality of life, and [N-terminal pro-B-type natriuretic peptide] NT-proBNP levels.
The results were bad. The group that received 120 mg of isosorbide had a trend toward lowered daily activity with a decrease in blood pressure. The activity level decreased progressively as the dose increased. I don't know, Clyde. Can you explain what happened here?
Dr Yancy: Well, we have to acknowledge that the hypothesis failed. But it may have failed in part because of the kind of nitrate that was used. Carl knows a lot about nitrates, and this once-a-day preparation leads to tolerance very quickly. So we may not have given it a fair test.
Nevertheless, I think what it really shows is how desperate we are to find something that will work for heart failure with a preserved ejection fraction. And you're right, with concomitant pulmonary hypertension, something that vasodilates should have been beneficial. But maybe that's not the place to go.
At least we can eliminate one variable from the equation and start our thrust for new efforts in a different direction. I'm just glad that we're able to answer the question, and we can stop the empiric therapy with these patients when it's not beneficial.
Dr Fuster: What do you think is happening physiologically?
Dr Yancy: Well, that's a loaded question, because what we're beginning to understand now is that not everybody who has heart failure with preserved ejection fraction has what we used to call diastolic dysfunction or diastolic heart failure. That's not always present. The important thing that comes up time and time again is that this is a heterogeneous disease, and likely with a heterogeneous substrate. Some will be due to cardiorenal interactions that aren't right; some will, in fact, be compliance issues; some will be ischemia. The most recent data say the concomitant presence of coronary disease in those who are symptomatic might be up to 80%. That may make us go back and take a closer look. It won't be just one thing that makes this work.
Dr Fuster: Comments, Carl?
Dr Pepine: I was surprised. Like most of the people here, I prescribed them. And this has even more implications. First of all, the doses of isosorbide that gained approval in ischemic heart disease were 120 and 240 mg. So one could question whether or not they really ever got up to what would be an effective dose. Clyde mentioned the issue of tolerance.
We have this new class of compounds, the soluble guanylate cyclase activators and inhibitors. And if there is a new treatment pathway that looks encouraging, it's that one. And the drug in this study is just starting up above and adding fuel to the nitrate path and more nitric oxide—it's an exogenous source not dependent on endogenous generation. Nevertheless, you should see something, and that was the disappointing thing to me.
Dr Fuster: Vera, any comments?
Dr Bittner: I'm not totally sure how regularly the people took the drug; because so many people get headaches from the nitrates, the compliance may not have been ideal. In the tables, it didn't look like it was dramatically different, but the drug discontinuations were numerically higher in the nitrate group than in the placebo group. So maybe that influenced things a little bit as well.
Dr Fuster: Except they got worse as the dose went up. Any further comments? Pat?
Dr O'Gara: One comment: I think this proves the value of a negative trial, doesn't it? We all wait for the trial to be positive and notoriety increases and advertising increases. This is really a very thoughtful, quote, "negative" trial. And I also like the fact that they use this accelerometer as an indicator of activities. We're sort of getting into this era where we're taking advantage of wearable devices from which people can transmit information that gives us a physiologic update on what's happening. I think it's spectacular, although it's negative. And I don't understand why.
Dr Yancy: We should not even say the word negative because you're still learning quite a bit from it.
Dr Pepine: It just didn't prove the hypothesis.
IVUS-XPL: Everolimus-Eluting Stents in Long Coronary Lesions
Dr Fuster: The next study is very typical of diabetic patients: long lesions in the coronary system. And the questions is how do you implant the stent. Do you follow these angiographically or do you use IVUS? I thought IVUS was used by most people, but that does not appear to be the case. This is the IVUS-XPL study[14,15] from Korea. It was a multicenter study with 1400 patients [Editor's Note: Speaker means to say 1400 not 14,000] from 20 centers in Korea with long lesions (≥28 mmm) guided by intravascular ultrasound vs angiography. What they found is that the degree of ischemia-driven target lesion revascularization was significantly increased when they used angiography and significantly decreased when they used intravascular ultrasound.
What is your experience in your own institutions, particularly in diabetic patients with long lesions? I thought that intravascular ultrasound was part of the procedure.
Dr Pepine: No. I've always been an advocate of intravascular ultrasound to deploy stents and to guide. But that's not the general practice, because it's costly and it also takes time. Most interventionalists today are interested throughput and moving patients through. I think they've largely abandoned it, and hopefully this article will stimulate them to start using it again.
Dr Fuster: Certainly the results are very striking in terms of revascularization. Any further comments about this particular study?
Dr O'Gara: One issue is the degree to which the angiographic-guided approach met standards because with this kind of a discrepancy in outcomes, you have to go back and say, well, how good a job did they do when guided by angiography alone? If I'm not mistaken, there's a discrepancy in the use of postinflation following stent deployment and the degree to which there could be a discrepancy in the way these things are performed in one country vs another.
Dr Fuster: They mentioned that they did intravascular ultrasound before and after.
Dr O'Gara: Yes, but in the angiographic arm, the use of postdilatation was far less than in the IVUS arm. Maybe the take-home message here is postinflation rather than the use of IVUS.
Dr Pepine: Compared with the way it's practiced in this country there was no [fractional flow reserve] FFR measurement. That would almost always be the case here.
Dr O'Gara: And an acceptable result here was 30% residual stenosis, which could also be discussed and debated among our interventional community. Part of the difference in results could reflect a substandard angiographic result.
Dr Pepine: Now that I think about it, there was no angiographic core lab.
Dr O'Gara: No.
River PCI: Ranolazine Use for Incomplete Revascularization
Dr Fuster: Anyway, so, something technical. I'd like to hear your comments about ranolazine. I remember reviewing the RIVER PCI study. This was presented by the group at Duke, Dr Karen Alexander, "Results from ranolazine for incomplete vessel revascularization."[16] This was just published in Circulation.[17]
If I recall, the original study[18] actually was in patients who had documented ischemia after incomplete revascularization. Some had angina, and some had not. And the end point was the degree of ischemic-driven revascularization or hospitalization, and the results were negative.
What they did here is to look at, by questionnaire, how [the patients'] angina [was]. These were over 2000 patients randomized into ranolazine and placebo, followed at 1, 6, and 12 months.
What is fascinating is both groups did equally well at the beginning, so whether they were on placebo or ranolazine, the angina decreased significantly. At the end, the results were absolutely equal. There was no difference using the Seattle Angina Questionnaire.
The placebo effect here is spectacular. What you think?
Dr Pepine: First of all, you'll hear another ranolazine study tomorrow,[19] ours, which is also identical in terms of outcome. And that was in the group of people who do not have obstructive coronary disease. And a lot of people believe it's the same syndrome operating here; it's just a microvascular problem that was the cause of their angina to start with, and the PCI or surgery didn't really change the course.
The other question, from the protocol-design standpoint, is how well the Seattle Angina Questionnaire performs in this kind of an environment. It's been well-validated, but its validation came principally from the VA hospital in patients with severe obstructive disease. I'm not so sure that's applicable. It's certainly not applicable to our study in patients who don't have obstructive disease. And I'm not so sure the population here in RIVER PCI.
I guess the final question is whether or not we're being misled in our ideas about this compound. If you remember, ranolazine started as a fatty-acid modulator to change metabolism, and then they figured out that its effect in that pathway was so minimal when given in the concentrations that were approved for angina that it must have another effect. It had this peculiar effect on the ST segment and QT that actually held up its approval for a while. And finally, they figured out the reason it was doing that is it had an effect on the late channel.
Then it was suggested that if, in ischemia, there's a problem with the late sodium channel, there would be more calcium entry, and the ventricle would be stiff. And then the capillaries and microvasculature would be impeded by this heightened pressure. That's all theoretical; there's actually no human proof for that hypothesis. But maybe that's all wrong.
Dr Fuster: I think what you are saying is that the drug did well in epicardial coronary disease and chronic angina—there are many studies—
Dr Pepine: Yes, we did multiple studies.
Dr Fuster: We are dealing with the microcirculation and with something much more complex than that. Is that what you're saying?
Dr Pepine: Yes. Maybe this is not the drug for that.
Dr Bittner: It would have been kind of nice to have the same data that we had in that accelerometer study earlier to see whether people's activity level changed with the two drugs at all. Because obviously, the degree to which you may experience exertional symptoms depends on whether you exert or not. It would be nice to normalize it that way.
Dr Pepine: We will have with the RWISE trial—it's not part of the AHA presentation or analysis.
PRADA: Preventing Cardiac Dysfunction During Breast Cancer Therapy
Dr Fuster: The final paper that I would like to have comment on is the PRADA study in patients undergoing chemotherapy for breast cancer. This paper was generated in Norway at the Oslo University Hospital. And Dr Geeta Gulati presented the paper.
We all know that the anthracycline and trastuzumab drugs can affect ejection fraction. There are some data in the literature suggesting that inhibition of the angiotensin pathway or even beta-blockers could be helpful in preventing or minimizing the ejection-fraction problem with these drugs.
Basically, 120 women with early breast cancer could be treated with candesartan (maximum dose of 32 mg/day), beta-blockers, and/or metoprolol (maximum 100 mg/day). Using a 2x2 factorial design, these drugs were given separately and together vs placebo. These patients were followed for a period of 10 to 64 weeks.
They used cardiac MRI to measure left ventricular ejection fraction at baseline. And the results were quite significant for candesartan in preventing a decrease in ventricular function; not significant at all for metoprolol.
The question is whether we have something to look forward to in the future, because these patients come to us after chemotherapy, particularly cancer of the breast but also other types of cancer. It's very well done. But the number of patients was not large, 120.
Dr Yancy: I'm delighted that someone has done this. There is so much empiric treatment that exists right now in this entire cardio-oncology space. There have been very few well-done clinical trials to answer questions as simple as this. And this is fairly minimal RAS blockade. Nevertheless, it looks like it may have made a difference. The numbers aren't large enough, Val. We can't extrapolate this into clinical practice.
But it certainly gives us the leverage to take it further and hope, because, as a practitioner who takes care of these women not infrequently, the consequences can be devastating. I mean, think about a patient who's already navigating breast cancer and now has heart failure. There is no such thing as a good morning with them. It's a tough, tough experience. But I think really it's just the first step. We've got to go further because there are a lot of complexities here.
Dr Fuster: Anne, any comments?
Dr Curtis: Well, were you saying they were demonstrating LV dysfunction and then got the drugs?
Dr Fuster: No. They started the drugs before the ejection fraction declined.
Dr Curtis: Before the ejection fraction changed at all. Then I think that's promising.
Dr Fuster: I call this primordial.
Dr Bittner: It's definitely exciting because like Clyde, I've had a number of these patients. And once they get very symptomatic heart failure, a lot of them don't get better. If we can somehow prevent that cascade from happening, it would be very exciting.
Dr O'Gara: I'm hopeful for a more precise future. It seems to me that—we took the drug from the RAS family, and it did okay, and the beta-blocker didn't. But can we get to a point where we're going to be smart enough to interfere with these molecules at a cardiac myocyte level and not at a systemic level? What is it about anthracycline and trastuzumab? There are compounds that have been tested to prevent this but they didn't pan out. But wouldn't this be a spectacular area where we could try to get very precise on a molecular level with blocking the effects at a cardiac focus so that it can have its cytotoxic effects in the right organ?
Dr Yancy: Right now the only thing we do to estimate risk is a crude measurement of ventricular performance before chemotherapy is given. We have to get better than that, so we can at least start treating these patients with medicines that are more sophisticated.
Wrap Up
Dr Fuster: Well, I think it's time to finish. We added some knowledge to our brains. We have SPRINT. The issue of troponins led us to ask, "What's happening at home, why doesn't the patient call the ambulance before we use troponins in the ambulance?" The issue of ischemic mitral regurgitation, still a lot to learn. Valve replacement appears to be the way to go. The Fifty-Fifty trial, using group therapy, maybe cardiologists will have to be much more involved in behavior modification.
Then nitrates in preserved ejection fraction didn't work. IVUS-guided PCI. I think you made a good comment that it's not always used when the length of the lesion is more than 28 mm. It should be. And then ranolazine—probably the disease is quite complex. Rather than dismissing the drug, we need to understand what is there.
Dr Pepine: We just don't know enough about that phenotype at the present time.
Dr Fuster: And the final issue of breast cancer, is interesting. Well, thank you very much to all of you.
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Cite this: The Cardiology Show From AHA 2015 With Dr Valentin Fuster - Medscape - Nov 11, 2015.
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