COMMENTARY

Heart Failure: AHA 2014 and Predictions for 2015

James L Januzzi, MD; Clyde W Yancy, MD

Disclosures

March 04, 2015

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Dr Clyde W Yancy: Welcome to theheart.org. This is Clyde Yancy, professor of medicine and chief of cardiology at Northwestern University here in Chicago. Joining me is Jim Januzzi from the Mass General Hospital, professor of medicine, director of the CCU still?

Dr James L Januzzi: Recent retiree, actually.

Dr Yancy: Both of us are here to share some insights with you about important heart-failure discussions that have occurred concurrent with the American Heart Association (AHA) Scientific Sessions that will be finishing up here in Chicago for this year.

Jim, welcome.

Dr Januzzi: Thanks very much, Clyde.

Dr Yancy: You know, this meeting was a little bit thin on heart-failure topics, but we still had more downstream discussion about the big news in heart failure, PARADIGM-HF.[1] Why don't we start by just getting your perspective on PARADIGM-HF before we talk about the new information?

Dr Januzzi: Sure. So, as the audience knows, PARADIGM-HF was presented at the ESC meeting, and yet we keep hearing about it. I think that speaks to the importance of this trial, which is really a sea change for how we are likely to be caring for our patients with heart failure. It bears repeating some of the primary outcomes while also giving us a glimpse under the surface, if you will, of the secondary outcomes and the effects, for example, on quality of life and specific issues that these patients sort of encountered during the trial.

New Information from PARADIGM-HF

Dr Yancy: So let's get right to that. Let me just read to you what came about as new information from the investigators:[2,3] In a statistically significant way, patients on LCZ696 were less likely to show symptomatic deterioration, less likely to need intensification of oral therapy or addition of IV therapy, less likely to visit the emergency department, less likely to be admitted to the hospital and when admitted were less likely to go to the ICU, less likely to require devices or surgery for worsening heart failure, and less likely to die prematurely, either suddenly or from worsening of heart failure, and even less likely to show biomarker evidence of cardiac wall stress and monocyte injury. That is a mouthful.

Dr Januzzi: Yeah, it sure is. Really, if you think about it, though, when you look at the primary, the top-line results, of the trial, 20% reduction in mortality, cardiovascular mortality, hospitalization, compared with enalapril, all of those follow-on findings are actually not that surprising, really. It confirms what we expect from a trial that showed such a profound effect on outcomes.

Dr Yancy: Particularly when you have an overwhelmingly positive study, it stands to reason that most other metrics of efficacy are going to go in the same direction.

Dr Januzzi: Right.

Some Questions to Address

Dr Yancy: Now, here is the important point. Now that we have these exclamation points on the data, how do we take this? Does it change anything about our enthusiasm or the fervor that we might have to get this available sooner rather than later, or are there still some things we need to deliberate before we actually make this real time?

Dr Januzzi: That's a really important question. I think it may add some more fervor to the discussion, but with a well-dosed contemporary comparator, LCZ696 improved mortality, which is something that we don't often see in our heart-failure trials, right?

Dr Yancy: Yes.

Dr Januzzi: And so the fervor is justifiable. I think that the benefits of the drug are very clearly established in this trial, it really is a pivotal and profound study. There are questions that we need to address. The fact that patients during the run-in phase—a significant number did not tolerate the run-in and therefore were not able to be randomized to the benefits of the drug. The question about angioedema, particularly in people of color, is still an open one. I think it's unlikely to be an issue but still worth our focus. I have no doubt that this drug is going to be in our armamentarium and probably reasonably soon.

Which Patients Will Benefit?

Dr Yancy: I would agree with you, but I do think that for those who are listening and trying to digest all the information, it probably is important to make a few points. It is necessary to first be able to tolerate a full dose of [renin angiotensin system] RAS blockade. About one in five patients was not able to go forward and be randomized to the actual therapy.

Dr Januzzi: That is the most important point to drive home. It is not as simple as just throwing a medication at a patient and assuming it is going to benefit them.

Dr Yancy: Right. So that requirement for full-dose RAS blockade is important (a de facto stress test). We don't have very much information for patients older than 75 years.

Dr Januzzi: Very true.

Dr Yancy: We don't have much information for patients who have NYHA class 4 symptoms, and our usual tendency when something like this happens is to take the patient that is teetering, not doing well, the older patient, the patient in and out of the hospital, and say I have something that might work. It actually might not work for that patient. Remember, these were primarily NYHA class 2 patients with what has been referred to as a sturdy blood pressure. I think if you want to keep anything in mind going forward it's NYHA class 2 and the sturdy blood pressure.

Dr Januzzi: Right, patients in PARADIGM-HF were on contemporary heart-failure therapies and yet their mean blood pressure at randomization was 120 mm Hg systolic. The patients who have called me since PARADIGM was announced are typically those patients who are well down the road with late stage C or stage D heart failure who are looking for the silver bullet. I think it remains to be proven if it will be for those patients. The caveat, given the way the drug works, is that we might actually see even higher potential for hypotension in certain patient subgroups.

Dr Yancy: Let me just finish off by giving you two other perspectives. On the one hand, I am incredibly intrigued with the notion of using the [angiotensin-receptor blocker] ARB/neprilysin-inhibitor combination upstream. Let's just say NYHA class 2 is upstream. And attenuating the progression to symptomatic class 3 and class 4, especially, for obvious reasons. Changing that natural history is very important from a public-health standpoint down to an individual patient standpoint.

Dr Januzzi: Sure.

Dr Yancy: But I also want to be certain that in our ebullient response to great information we don't forget to take the time to continue to be deliberative as we review all the data.

Dr Januzzi: Yes.

Dr Yancy: This is going to be a dynamic that will change the way we practice, and we should really think about all aspects of this before we go forward.

Dr Januzzi: The pros and cons. These are exclamation points on an already nicely developed story, and it is now an opportunity to look at things in a deliberate fashion to see what we can do for our patients because, as I said, this therapy is coming and we will be using it.

Dr Yancy: So let's talk about some other more exploratory ideas that came about at this meeting. There was a fabulous clinical-science session at AHA that started off with PARADIGM-HF and then revisited stem-cell therapy. It addressed spinal-cord stimulation, and then it ended with yet another attempt at structurally reverse-remodeling the heart.

Dr Januzzi: Yeah.

PreSERVE-AMI

Dr Yancy: Let's break those down one by one. I had the privilege of being the discussant for the stem-cell study, so I will just briefly summarize that in this study,[4] using a cell population that had been previously studied, CD34-positive cells, harvested from bone marrow but harvested in such a way that it accentuated the property of those cells that would uniquely focus on homing toward a region of scar ischemia. There was then the administration of those cells at doses of 10 million up to 20 million to individuals who were post-MI. They had an acute event, with an ejection fraction no greater than 48%.

Follow-up for those patients looking at clinically important outcomes demonstrated a very modest improvement in LV ejection fraction. There actually was a numerical difference in death, which wasn't a primary end point (zero versus three), but nevertheless it was statistically significant.

And then importantly, for a marker that we would have liked to see influenced—that is, the extent of the ischemic burden using [single-photon-emission computed-tomography] SPECT imaging—there was no improvement. But yet, again, it was another small step in the direction of this stem-cell concept to regenerate myocardium.

What are your thoughts about this whole process?

Dr Januzzi: Regenerative medicine is such a hot topic, and while drug therapies for heart failure continue to evolve, there is a rising enthusiasm to look at either stem cells, whether they are CD34-derived, bone-marrow–derived, mesenchymal stem cells, other forms, either injected via coronary routes or injected directly into the myocardium, to regenerate muscle that has been lost.

There are also gene-therapy approaches being examined, and so these parallel approaches are exciting prospects, but the field has a long way to go. When you see the kind of improvements that we are seeing in the PreSERVE study, a phase 2 trial, it is hypothesis-generating, and it sets the stage for the pivotal, randomized, controlled trials that we desperately need in this area.

Dr Yancy: Two points here, and you touched on the big one: we are still wrestling with which cell, if we are going to use bone-marrow–derived cells, what route of administration, which patient, and what is the timing?

Dr Januzzi: Absolutely.

Dr Yancy: There are so many variables in that equation that are in a state of flux. Certainly, I endorse the research because I think we need to keep moving, but I am impressed at the challenges. At a minimum, because these results were favorable for LV ejection fraction, you could appropriately power a phase 3 study with LVEF as an end point, but at the same session, I said maybe what we should do now is pause, because we have clearly demonstrated that this is safe. The earlier concerns that maybe something totally untoward would happen.

Dr Januzzi: With immunogenicity, right?

Dr Yancy: So we demonstrated it is safe, and we have demonstrated that it is feasible that you can harvest bone-marrow cells, you can obtain a cell population of interest, administer it. The mechanics of doing this have been overcome.

Now maybe we pause and say, okay, so what is our highest yield direction at this point? I don't know what is going to happen.

Dr Januzzi: That is a challenge, because there are a lot of different parallel efforts right now. In my role at the Harvard Clinical Research Institute, we are bringing a stem-cell trial forward. There are trials that are ongoing right now using different techniques and, as you rightfully point out, these pivotal studies are sorely needed, but in general they are relatively small, and the techniques that are being used are very different, and so finding a conclusive approach is very necessary.

Defeat-HF

Dr Yancy: There were two other things that were discussed in this session. One was spinal-cord stimulation and the other was an attempt to acutely or procedurally reverse-remodel the ventricle. The spinal-cord stimulation was one of several studies, a couple of which we saw at the European meeting, where either you are using a vagal approach or a spinal-cord approach, but the end result being can we modulate the sympathetic nervous system or autonomic tone in some way that would create favorable changes on the ventricle.

Certainly, there are animal data to suggest that that might work, but efforts to show this in man have been complex and the findings have been inconsistent, and what was different in the Defeat-HF study,[5] brought forward by Dr Zipes and his colleagues, is that you can do something like this very carefully with a controlled population. But the results were completely neutral, totally superimposable [event curves].

Dr Januzzi: Very disappointing.

Dr Yancy: One of the questions that was raised, which I thought was quite poignant, was how can you be certain that you have actually modified autonomic tone? That is worth considering, whether it is heart-rate variability or some biomarker. I don't know.

Dr Januzzi: It is a hard thing to measure, and that is the point that the discussant made. How do you know that you have delivered the therapy you think you are delivering? That is an important take-home with these novel therapies. Apropos the next study we are going to discuss, sometimes when we do something therapeutically and we think we are achieving one therapeutic goal something else may be happening, and sometimes we are not exactly sure where the target for therapy really is.

Dr Yancy: Particularly in this field of manipulating autonomic tone. I worry that there is so much redundancy in that system, so many feedback loops, that the durability of any effect is a question that has to be raised.

Dr Januzzi: Certainly early concerns about the potential for proarrhythmia in this setting have been allayed. I think we know it is not going to increase risk, but the fact that the results were so superimposably negative is disappointing.

AUGMENT-HF

Dr Yancy: Let's go to the last study. For quite some time everyone has had the following logic: if ACE inhibitors or RAS blockers and evidence-based beta-blockers reverse-remodel the ventricle, then patients have better outcome. [Cardiac-resynchronization-therapy] CRT reverse- remodels the ventricle. Aldosterone antagonists reverse-remodel the ventricle. Maybe the target is finding other approaches that will reverse-remodel the ventricle. In a way, STICH[6] was about surgical reverse-remodeling. We know that there have been ventricular constraint devices, tethering devices, all attempting to get to the same place.

Dr Januzzi: Nothing has worked.

Dr Yancy: Right. And so now we have this fascinating concept of using inner plugs made out of Algisyl. It was in the AUGMENT-HF[7] study?

Dr Januzzi: AUGMENT-HF, yeah.

Dr Yancy: What did you take home from that?

Dr Januzzi: It is remarkable and, again, it begs the question: exactly how is this benefiting the heart? Basically what was seen with these implants, which were put in through a ministernotomy, is that the myocardial performance was enhanced such that patients had improvements in 6-minute-walk tests, improvements in their maximal oxygen consumption on cardiopulmonary exercise testing, and there was some impact on quality of life. This myoplasty, if you will, using alginate-derived substances, might very well have had a significant improvement in their heart-failure status.

Dr Yancy: It really is fascinating. It is interesting to think about the way this session took place because both the primary investigator, someone we immensely respect, Doug Mann, and the discussant, Mariell Jessup—can you get a better one-two punch?—started with the same theoretical concept, Laplace's law, and it is really a joy to be taken back to physiology and remember that this is the crux of LV dysfunction, these issues of wall stress.

Dr Januzzi: Absolutely.

Dr Yancy: And any way we can modify wall stress ought to be better, but as we have learned in other paradigms in medicine, even though you have a target, modifying it doesn't always give you the desired clinical outcome.

Dr Januzzi: The question that continues to stick in my mind is: is this a mechanical benefit, or is there some other biological response that is resulting in changes in myocardial structure or function that led to these findings? I think that is an open question.

Dr Yancy: And think about this. The actively intervened-upon group had a limited median sternotomy and a surgical procedure. They were aware of the procedure and the control population, a similar number of patients, did not undergo the operation. So there is no blinding at that point, and you have got a surrogate marker.

That is an appropriate design for a pilot or exploratory study, but you have to factor in that the patients/physicians knew what was expected.

Dr Januzzi: There is no question the power of positive thinking can be quite substantial, and if patients know that they received the active treatment then there could very well be an impact, especially the 6-minute-walk test. The maximal oxygen consumption is a little bit harder to game. Still, there is no question that it's a concern, and a randomized design is going to be important next time.

Dr Yancy: Remember, the magnitude of benefit on the maximal O2 consumption paralleled exactly what was seen in the landmark CRT studies, so we can't dismiss this response.

Dr Januzzi: No.

A Look Ahead

Dr Yancy: Let's just finish up. What do you think is going to happen in heart failure? Where are we going? If you and I were sitting here a year from now, what do you think would be different?

Dr Januzzi: Well, I think we will be seeing LCZ696 with a different name coming forward in the next year, and our experience with the drug will grow. I think that there will be some expected and unexpected outcomes from this. I think there will be a learning curve associated with its use. Clinicians should be aware that LCZ696 through its effects causes an intended increase in BNP because it inhibits its breakdown. NT-proBNP goes down, so physicians are going to have to learn the difference in how to look at patients using these biomarkers.

Another heart-failure drug, ivabradine, is currently being considered for regulatory submission. This is a drug that blocks IKr channels

Dr Yancy: The "F" channels.

Dr Januzzi: The funny channels, in the sinoatrial node leading to heart rate reduction. In the SHIFT trial[8] it showed a significant reduction in adverse outcome, particularly in patients with faster heart rates. This drug may be coming forward.

We have the pivotal phase 3 trial looking at serelaxin in acutely decompensated heart failure, and my hope is that down the road we are going to start seeing therapies for heart failure with preserved ejection fraction [HFpEF], but I don't think we are going to see anything like that in the next year.

Dr Yancy: But the trial using LCZ696 in HFpEF has been initiated.

Dr Januzzi: It has. The PARAGON study is launched, and imagine if we have one drug to rule them all? One drug for both reduced and preserved ejection fraction. It would be a remarkable step forward.

Dr Yancy: Well, thanks. This has been a fabulous conversation, and I hope those of you who are listening to us have enjoyed this discussion about heart failure, not only the information that was reviewed here at the AHA Scientific Sessions 2014 but our own independent views about where we think the needle is going to be in the future. Thanks for your time and attention.

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