Editor's Note: Douglas L. Mann, MD, Lewin Chair and chief, Cardiovascular Division at Washington University School of Medicine and cardiologist-in-chief at Barnes-Jewish Hospital in St. Louis, Missouri, is the principal investigator for the AUGMENT-HF trial. He presented the latest findings from that study at the 2015 American Heart Association Scientific Sessions, where Ileana L. Piña, MD, MPH, interviewed him.
Dr Piña: Hello. I'm Ileana Piña from the Albert Einstein College of Medicine and the Montefiore Einstein Medical Center in the Bronx, New York.
I am here at the American Heart Association Scientific Sessions.
A Bit About Remodeling
You hear the word "remodeling"—we use it a lot. We use it after myocardial infarction (MI): "Let's not let that heart remodel." We use it in the heart failure patients: "We want to prevent further remodeling." We also would love to reverse that remodeling.
This isn't like remodeling your kitchen, where it looks better when you're done. The remodeling of the heart doesn't look so good. That further remodeling is really associated with bad outcomes. And we have been trying to reverse remodeling since we understood it better, that it is a combination of hypertrophy and dilatation. It's a response of the heart to an injury. And we've tried to reverse it even in hypertensives, who have left ventricular (LV) hypertrophy.
But there are other ways, and the drugs often don't make that difference.
Joining me today is Dr Doug Mann, a very good friend and the chief of cardiology at Washington University in St. Louis, and at the Barnes Hospital, which is one of the most fabulous hospitals in this country. Doug, welcome.
Dr Mann: Ileana, thanks for having me. I'm pleased to be here.
Dr Piña: You had an exciting morning today. You were presenting your work. Tell us a little bit about the theory of an injection to try to either prevent or halt remodeling.
Surgical Approaches
Dr Mann: There have been a number of different surgical approaches to reverse remodel the ventricle, the most prominent of which has been the Batista procedure,[1,2] where they literally cut a piece out of a heart and stitched it back together. The Dor[3] procedure, which removes an LV aneurysm, is a similar approach. So one approach is to actually make the ventricle smaller to reduce wall stress.
Then, another approach that we were involved in was these epicardial constraint devices.[4] They are a little complex to explain; they reduce wall stress by decreasing the so-called transmural pressure, the pressure across the ventricle. And those devices showed promise but ultimately didn't pan out.
A New Approach—"Brown Seaweed"
The device that I've been working with most recently is called Algisyl®; it's a calcium alginate hydrogel, basically brown seaweed.
Dr Piña: That's a good way of putting it.
Dr Mann: It's a little fancier than that, but it's dried from seaweed. It's a proprietary hydrogel that when mixed will form a solid hydrogel in the ventricle. The premise of the Algisyl study[5,6] was that by reducing wall stress, by increasing wall thickness and—according to the law of Laplace—reducing wall stress, one could favorably influence the untoward natural history of heart failure.
Dr Piña: And this Algisyl alginate, does it have any stretching power?
Dr Mann: Once it is injected into the ventricle and it forms a polymer, it's relatively inflexible. It does have some elasticity, but it more or less forms a solid sphere that's not too deformable.
What's the Difference?
Dr Piña: I remember when we started doing the Batista procedure. Patients were hard to manage after the Batista procedure because their ventricles developed both diastolic and systolic dysfunction, and you couldn't keep them dry enough, and you couldn't keep them wet enough. So we would see blood pressures that were up and down. How is this different?
Dr Mann: As I alluded to, surgical resizing to reduce wall stress is completely different. As you pointed out, it does change the material properties in the ventricle. Just making it smaller doesn't make it more elastic. In essence, they took a bad heart failure and just made a smaller heart that couldn't accommodate the volume that we see in these patients. So a lot of them had diastolic dysfunction, and there was really no improvement in systolic function. It was the operation that incorporated the worst of two different worlds.
Animal Models
Dr Piña: Did you start this work with an animal model?
Dr Mann: First of all, it's important to emphasize that alginate has been around for years. People use it as a filler substance. It's biologically inert and has no impact on the immune system, so it's a very safe material to use.
There were a number of studies[7] in dog models using the so-called "Sabbah model" of microembolization, where you inject microspheres down the coronary arteries. It's like micro heart attacks. The dogs' hearts dilated. When they were given the Algisyl beads, it prevented the remodeling that occurs.
Dr Piña: How long after the bead injection?
Dr Mann: Typically Dr Sabbah would look at the animals in 3 months. Commonly the readout is about a 3-month period, so a prolonged period of time. It's certainly not an immediate effect on the ventricle.
Dr Piña: Do you think that there's some remodeling that's happening already? Obviously the injection of the beads and causing microinfarcts—there's some remodeling already happening.
Dr Mann: For sure. When you kill off muscle cells, there's inflammation, cell death, and eventually those dog hearts will undergo forward remodeling quite significantly with very significant changes in their LV volume. When the Algisyl was implanted immediately after the microembolization, it just prevented that remodeling.
Timeline in Humans
Dr Piña: Interesting. How does that relate to, let's say, time after an MI in the human?
Dr Mann: Typically the evolution of LV remodeling, as you are well aware, occurs over a sort of a 3- to 6-month period in patients. Today, with modern medical therapy, which includes beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, statins, and aldosterone antagonists, that growth of remodeling is certainly a lot less.
The other big intervention, as you're well aware, is the percutaneous coronary intervention immediately after infarct. We no longer see aneurysms. In the old days, and you and I are both old enough to remember the LV aneurysms, we used to get a lot of LV remodeling. So the absence of that sort of akinetic scar has also reduced the amount of remodeling, though there's certainly a significant amount from 3 to 6 months for the postinfarct.
Dr Piña: The science has changed. I mean—we've changed physiology. Isn't that interesting?
Dr Mann: We have.
The AUGMENT-HF Trial
Dr Piña: So tell me about your study that you presented this morning.
Dr Mann: The AUGMENT-HF Trial—it was a 6-month study. Last year, at the American Heart Association, we presented the official findings of the 6-month study. The major findings were that peak VO2—and I realize that's near and dear to your heart, we used the peak VO2 as the primary endpoint—there was a significant improvement in peak VO2 at 6 months.
Today I presented the data on the peak VO2 at 12 months. Not only was the effect durable, but it also increased from what we saw at 6 months. So the overall improvement was about 2.1 mL/min/kg, which is a substantial improvement.
Dr Piña: That's higher than we've seen before.
Dr Mann: It's a little bit better than cardiac resynchronization therapy (CRT). I don't tell our friends about that, but it's about on par with CRT. Importantly, it moved patients from a peak VO2 of 12 to 14 mL/kg/min.
The other thing that we did for this trial was to look at anaerobic threshold, which is less subject to patient volitional effects (and I know this is also near and dear to your heart). But we also showed an improvement in anaerobic threshold at 12 months.
Dr Piña: That's important.
Dr Mann: Overall, very robust endpoints. It's important to emphasize that this is, in essence, an open-label trial. The patients who got the surgery with the Algisyl devices were, in essence, unblinded. The patients on the standard medical therapy knew that they weren't getting therapy, and the patients who got alginate did, which is why we picked peak VO2 as a robust endpoint. We thought it was the least subject to—
Dr Piña: Good for you. I really congratulate you on picking that because other people get a little scared of picking peak VO2. But, as you know, if you do it right, it does a lot.
Dr Mann: We had a terrific core lab that made sure that there were two separate measurements, so the variability was taken out of it. The patients were able to perform the same amount on two separate tests.
Clinical Results
Dr Piña: How did the patients feel?
Dr Mann: The patients said, not surprisingly in an open-label study, that they felt a lot better at the beginning of the study, and about 75%-80% of the patients were New York Heart Association class III or IV, which is fairly significantly symptomatic.
At the end of the study, of the patients in the Algisyl treatment group, 85% were either New York Heart Association class I or II. Overall, there was a highly statistically significant difference when compared with standard medical therapy alone.
Dr Piña: And what was the background therapy like in the groups?
Dr Mann: Background therapy reflects the quality of the investigators—95% were on beta-blockers, 90% were on ACE inhibitors, about 50% were on aldosterone antagonists. So, we had a very well-treated, contemporary group of heart failure patients that were well-treated by the site investigators.
Durability of the Response
Dr Piña: So this is a 12-month result, now, of the injection. And it's a one-time injection?
Dr Mann: A one-time injection. And the purpose of the 12-month follow-up was to really see the durability of the response. On theoretical grounds, the alginate beads should remain in the heart. There's no way to enzymatically adjust them; the body doesn't have the enzymes to do that. But we wanted to get a feel for the durability and also what any kind of long-term complications might be.
Dr Piña: What happens to the size of the ventricle on echo?
Dr Mann: One thing that didn't track as well with the peak VO2 measurements was that we saw stabilization of ventricular modeling, but compared with the control group, there was really no significant difference. We had very small numbers of patients using 2-dimensional echo, which has big confidence intervals. And the other thing that happened, as you know, is that the control group actually got a little smaller, too, probably reflecting the good care by the physicians. So compared with the control group, we weren't able to show a difference.
AUGMENT-HF II
Dr Piña: So what's next? Give me your crystal ball.
Dr Mann: Thank you for asking that. We've just gotten approval from the US Food and Drug Administration to do AUGMENT-Heart Failure II. This will be a trial of about 260 patients. Again, we will use a very similar design—the patients will be randomly assigned one-to-one to receive the Algisyl implant vs standard medical therapy. And the endpoint, again, will be peak VO2, but we'll also look at things that matter to patients, such as heart failure hospitalizations as well as overall mortality.
Dr Piña: So you're going to look at some outcomes.
Dr Mann: Absolutely.
Quality of Life
Dr Piña: What happened to quality of life? Did you measure it in the short term?
Dr Mann: For quality of life, we used the Kansas City Cardiomyopathy Questionnaire (KCCQ), and we used the two different domains in the KCCQ. And, again, they were statistically significant. But I would again emphasize that this is an open-label trial, and so sometimes it's subject to patient bias. But, again, it tracked what we were seeing with overall New York Heart Association and the peak VO2.
The Injection Procedure
Dr Piña: And the injection is done open, right?
Dr Mann: The company, LoneStar Heart, is working on a percutaneous device to inject it endocardially, which I think would expand the patient population. But right now it requires a limited LV thoracotomy. And then the surgeon will identify the midwall of the beating heart. It's important to emphasize that this does not require bypass surgery.
Dr Piña: That's an advantage.
Dr Mann: Yes, a huge advantage. They identify the midwall, and then they perform a series of injections of about 0.3 cc of the Algisyl into the midwall of the ventricle. And they start in the anterior atrioventricular groove and then move posteriorly and align. And on average it's about 15 implants per ventricle, depending on how big it is.
Dr Piña: How do they decide that? How do they know?
Dr Mann: They try to do it a centimeter apart, so depending on how big the heart is, they just do enough injections to complete—
Dr Piña: Consistent separation.
Dr Mann: Yes. One centimeter apart.
Dr Piña: How long are the patients in the hospital?
Dr Mann: The procedure itself takes about 80 minutes, and depending on how sick the patient is before, the length of stay can vary from anywhere from 3 days—and then we've had a couple of people who've been much sicker and haven't been able to get out of the ICU for up to 30 days. But, again, it really reflects how sick the patient is going in.
Dr Piña: That's the group that we struggle with. And we're trying to make decisions whether to put an LV assist device (LVAD), or whether to transplant.
Dr Mann: The alternative therapy here would be LVAD or transplant. We think this is a little less invasive than an LVAD.
Dr Piña: It may be an interesting endpoint to look at.
Dr Mann: The number of people that you prevent from going to LVAD or transplant. Great idea.
Dr Piña: Have you thought of a sham?
Dr Mann: The difficulty with performing anterior thoracotomy in a patient just to give a sham injection, we weren't at equipoise with that particular decision. I think it would be hard to talk people into doing that. If they get the percutaneous device, where you can inject it endocardially, and we've learned so much from the stem cell field that I think developing that technology for the use of injecting Algisyl should be relatively straightforward. My hope is that we can make it and put it in the hands of the cardiologists and not in the surgeons.
Dr Piña: That always helps. I have to say that I've so admired you through the years.
Dr Mann: You're too kind.
Dr Piña: No, it's true. You've been very consistent on your pathway to figuring out how the heck are we going to stop the ravages of this disease. In the Bronx, I see these young people, not the patients I was used to, the 70- and 80-year-olds. These are 50- and 60-year-olds.
Dr Mann: It's heartbreaking. The other thing is that with the advent of all of this chemotherapy now for young women with breast cancer, we're seeing a lot more dilated cardiomyopathy.
Dr Piña: I just saw a "Get with the Guidelines" paper on heart failure in women, showing that 67% of the chemotherapy-induced heart failure is in women. And you have to think that that's the breast cancer field.
Dr Mann: Oh, definitely.
Dr Piña: Well, if we could do something with them. When are you going to start this new trial?
Dr Mann: We don't know yet. The company is still going through some of the fundraising efforts, but we hope to start it early next year.
Dr Piña: I really congratulate you on a lot of great work.
Dr Mann: Thank you so much.
Dr Piña: I want to thank Dr Mann for joining me today. I hope that you have gleaned some interest in this field. Certainly, remodeling is not going to go away. As long as we have cardiovascular disease, this is a part of our life.
This is Ileana Piña signing off. Thank you for joining me today.
Disclosure: Douglas L. Mann, MD, has disclosed the following relevant financial relationships: received grant/research support from: National Institutes of Health; serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: BioControl Medical Inc; Eli Lilly and Company; Corvia Medical; served on the Scientific Advisory Board for: Cardioxyl Pharmaceuticals; MiRagen Therapeutics Inc; LoneStar Therapeutics
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Cite this: AUGMENT-HF: A Novel Approach to Cardiac Remodeling - Medscape - Jan 07, 2016.
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