Heart failure in which left ventricular ejection fraction recovers into the normal range has many unknowns. Andrew Perry, MD, discusses key management strategies with Jane Wilcox, MD, of Northwestern University in Chicago, in this episode of the AP Cardiology podcast.
A transcript of the podcast follows:
Perry: Hi, everyone. It's Andrew. I hope everyone's staying safe and healthy through the coronavirus pandemic. Before we get started with today's episode, I want to give a shoutout to the . If you're not already listening to their podcast or checking out their website, you should be. They are really good medical educators, Dan Ambinder and Amit Goyal. They put together a really good show, and they put out a lot of material. I highly recommend that you head over and check out their stuff.
In today's episode, I met with Dr. Jane Wilcox -- she is from Northwestern University -- and we discussed about the topic of myocardial recovery. You may have seen patients who have heart failure with reduced ejection fraction, who then normalize their ejection fraction after medical or device treatments, not in response to ventricular assist devices or heart transplants. She has a myocardial recovery clinic up there at Northwestern and does a lot of research in this area. I had a number of questions with her about how to think about those patients and certain clinical questions that come up.
If you're enjoying AP Cardiology, I would ask for a favor that you give the show a shoutout on your social media channels or head over to iTunes and leave a review on the webpage. It really helps find new listeners for the show. With that, we'll get started with today's episode.
Perry: This is AP Cardiology and this is your host, Andrew Perry. Thank you for meeting with me today, Dr. Wilcox. May I have you introduce yourself for our audience?
Wilcox: Thank you so much, Andrew, for having me. My name is Jane Wilcox. I am an assistant professor at Northwestern University Feinberg School of Medicine, in Chicago, Illinois. I direct our myocardial recovery program. I'm an advanced heart failure cardiologist, so I see patients who are very sick, who need a transplant and an LVAD. I specialize in patients who have stage C heart failure and we focus on recovering their ventricular performance. So I'm glad to be here with you today.
Perry: Great. Perfect. Thank you so much. This is a topic I've been wanting to do for a little while now. I think it's a topic, an issue, of myocardial recovery -- or patients who recover their ejection fraction -- that doesn't get a lot of attention.
Wilcox: Yeah.
Perry: Let me start with presenting a typical case that I've encountered. I have a 64-year-old woman. She has a history of a non-ischemic cardiomyopathy diagnosed about a year ago. Her ejection fraction at the time of her diagnosis was 30%. After a few months of therapy with lisinopril, metoprolol, and spironolactone, with some Lasix [furosemide], her ejection fraction was still 35%, so she had an ICD implanted for primary prevention. At that time of her ECG, she has a right bundle branch block morphology with a QRS of 110.
She comes back to see us about a year later and an echo at that time demonstrates that her ejection fraction is now up to 55%. In the interim, she's been able to come off of her Lasix, but she remains on her lisinopril, metoprolol, and spironolactone.
I think one basic question that comes up when I see these patients is how do we even categorize her at this moment? Now that we're seeing her, her ejection fraction has improved. Is she someone that we still talk about in terms of HFrEF, heart failure with reduced ejection fraction, or HFpEF [heart failure with preserved ejection fraction], or is there another way that we should be categorizing her?
Wilcox: These are all great questions. I think the first point about this lady is that she has recovered her ejection fraction despite us failing to do forced titration of medical therapy. That's our first point. We know from the that the appropriate doses of guideline-directed medical therapy in patients with reduced ejection heart failure is abysmal. It's 1%, right? She has responded to lisinopril, which really isn't the standard of care. Right now, the standard of care would be an ARNI [angiotensin receptor-neprilysin inhibitor], high dose, either metoprolol or carvedilol, and then the MRA [mineralocorticoid receptor antagonist], as you mentioned.
But she has in fact improved her ejection fraction, so she has recovered cardiomyopathy, and we would categorize her as heart failure with recovered EF. She is phenotypically like a reduced ejection heart failure patient with a recovered ejection fraction, so HFrecEF, or heart failure with improved ejection fraction. Those are the two common nomenclatures that we've seen.
Perry: HFrecEF or heart failure with recovered ejection fraction. You're stating that those are phenotypically different. I think there was also some data that they are even biochemically, or with their circulating catecholamines, with their BNP, with those sorts of levels, that they are also different in those respects. Could you describe how this category is phenotypically and maybe biochemically different from those two other categories?
Wilcox: I would step back little bit. This patient is sort of always a reduced ejection fraction cardiomyopathy patient, so she will be phenotypically similar to those reduced EF patients, just that she has responded favorably to guideline-directed medical therapy, so neurohormonal antagonists. She, in fact, does accrue benefit from these medicines. We'll talk a little bit, I imagine, about how long she needs to stay on these medicines and could we stop some of these medicines. She really is in remission from her heart failure with reduced EF, with improved ventricular performance.
As far as the biochemical question, definitely lower levels of circulating biomarkers like NT-proBNP, galectin, signs of fibrosis, ST2. So definitely in remission with lower levels of biomarkers, but still what we would call at-risk for future heart failure events.
I really like the oncologic corollary here. When we think about patients who are 5 years, 6 years out from their breast cancer, they are we think out of the woods, but we still follow them very closely for recurrence. That's how we should be thinking about this heart failure population.
Perry: That's great. You used the words, "She's in remission right now," thereby implying this corollary with oncology. There is this idea of myocardial remission versus myocardial recovery that's discussed in the literature.
Wilcox: Right.
Perry: Could you elaborate on them?
Wilcox: Yeah. I have thought about this a lot -- and I talk about this with all my friends, and we geek out a little bit -- and the answer is it sort of doesn't matter. I think as long as the patient is feeling better, they feel recovered. Right? When it matters is when we think about implications for long-term medical therapy. If a patient truly is "recovered," that implies that they don't need long-term medical therapy with neurohormonal antagonists. I think we, in 2020, don't have the data to differentiate who is recovered and who is in remission.
I think my friend and mentor Doug Mann would say... he wrote a several years ago now. The best definition of recovery, true recovery, that I've found over the years is: The structure and function are both normal. At a cellular level, things are working normally, structurally the heart has returned to its normal wall tension state, so the diameter has shrunk down, the thickness has regressed, and the function is normal, so that would be ventricular performance. Again, we just don't have perfect ways to say, "You are recovered," versus, "You are in remission." I think, as a field, right now we treat patients as they are in remission.
Perry: Beautiful. Thank you.
Wilcox: Sure.
Perry: Now, thinking about our patient that we described here, all I mentioned was that she had a non-ischemic cardiomyopathy. She had a cath with some luminal irregularity, so really no obstructive coronary disease. When we're thinking about patients who recover their ejection fraction, are there certain types of non-ischemic cardiomyopathy that are more common than others to recover their ejection fraction?
Actually, maybe even more broadly speaking, maybe taking a step back first is the question of patients with ischemic cardiomyopathy versus those with a non-ischemic. Are there differences in those groups and how frequently they recover their ejection fraction?
Wilcox: This is a great question and it's a little muddy because the data that we have, most of it is either observational or retrospective single-center studies or consortium. When we look at the data about sort of the percent of who recovers and responds, it's all based on that population.
If you look at the , which is an advanced population, a referral population, the incidence of recovery there is less than 10%. Then you think, "Well, it's not that common. It's more likely in non-ischemics." Then you look at other studies, observational studies. We look at the Emory study or clinical trial data from Val-HeFT. Or even data from Italy, they have some registries there where recovery may be more common in the sort of 30%. Really, when we delve into this, the predictors of recovery -- or things that would be associated with recovery -- are shorter duration, non-ischemic status, women, which sort of fits with women being more likely to have non-ischemic cardiomyopathy. Smaller volumes, so less adverse remodeling if someone is not super-dilated, they don't have a lot of scar on their MRI, they have the ability to tolerate medical therapy. Those are all things, when I see that clinically, I talk to my patients and say, "Well, you've got some markers that look like you'll respond favorably to GDMT [guideline-directed medical therapy]."
Recovery is one of those things that's always kind of diagnosed in the retrospectoscope. We don't have great ways of saying, "Based on your tumor markers, Mrs. Jones, you are most likely to have an X percent here." We're a little bit behind oncology, but my hope is that we get there in the future.
Perry: Gotcha. Since you also mention that, or touched on the point of genetics in that point, when you're seeing these patients -- and we don't have an analogy for tumor profiles for our patients with heart failure -- are there any genetics, or what information do we have currently about genes or polymorphisms that would indicate a higher likelihood of recovery amongst those patients?
Wilcox: This is an active area of my research profile. I think what I do clinically is every patient who has DCM, or dilated cardiomyopathy, who is less than 55, we clinically test those patients with a clinically-available profile that looks for about 90 candidate genes that are known bad actors and are associated with cardiomyopathy.
If a patient has a really bad actor -- and some of those genes might be lamin, so laminopathies, Filamin C, SEM5A, really arrhythmogenic genes, or genes that have been studies that the natural history of that disease is this progressive heart failure, fibrosis, arrhythmia -- that's a different conversation than a patient who has maybe a mild cardiomyopathy and a truncating variant in titin. Titin is the most common. It's the largest protein in the sarcomere and is probably the most common cause of dilated cardiomyopathy, or alcohol, or peripartum.
There's some work that titins actually respond very favorably to GDMT. Not always. That's a different conversation that I have with patients. That needs to be fleshed out in a much more robust manner, but that's the clinical conversation I have with patients.
Perry: Gotcha. Very cool. Then speaking of, I think, perhaps most of the clinics that I've worked in have not had the emphasis -- or perhaps even the availability or the focus -- to be ordering genetic profiles on all the patients with reduced ejection fraction. In part, we treat everyone with guideline-directed medical therapy: ACE inhibitors, beta blockers, MRAs, ARNIs -- if we're able to get them approved -- or et cetera for our patients. When we're thinking about our arsenal of GDMT, are there certain medications within that, that are more likely than others to lead to recovery of ejection fraction?
Wilcox: Again, a really great question and something that we are trying to figure out. It's hard to do these kind of clinical trials, "Who would respond favorably to a certain medicine as opposed to another?" simply because of the way our trials have been done in the past. It's always an add-on, so it's dapagliflozin [Farxiga], or SGLT2, in addition to background medical therapy. Vericiguat in addition to background medical therapy. And so we're doing these add-on trials. I think it's a little tricky and there may be a lack of equipoise to do a beta-blocker only trial, right?
Perry: Yes.
Wilcox: I think the way that we might answer these questions in the future would be trials where we start to take away medicines in a phased manner to sort of identify patients who may just respond favorably to a beta-blocker or an ARNI compound, for example. Right now, we really can't say, "This person is more likely to respond to an ARB [angiotensin receptor blocker] as opposed to a beta-blocker." I will say that I try to get patients on the ARNI compound and an evidence-dosed beta-blocker. I try to do that for all my patients.
The best data we have potentially when we think about genetic cardiomyopathies may be in Duchenne muscular dystrophy or Becker muscular dystrophy. There's data there that ACE inhibition and MRAs will actually delay progression and reduce scar in young boys who are age 9, age 19. This is sort of a protracted course that we could look at certain types of genetic cardiomyopathies. But as of right now, I think we have this one-size-fits-all approach and the way that we answer this [in the] future may be in a withdrawal approach just because of the lack of equipoise.
Perry: Speaking of trials about withdrawal, there was a trial recently within the last couple of years, the , where they took patients with a dilated cardiomyopathy who had recovered their ejection fraction, normalized their volumes, and they attempted to wean their medications. For those patients, it was in a small trial of like 50 patients. After weaning medications, those patients who were randomized to weaning had increased in their volumes and decreases in their ejection fraction.
Wilcox: Over a very short period of time, actually, too.
Perry: Yeah. It was over... what was it?
Wilcox: Eight weeks.
Perry: Eight weeks.
Wilcox: Yeah.
Perry: That was not clearly a very optimistic signal in terms of withdrawing medications, I guess. Coming back, are there other patients that we might even feel comfortable starting to withdraw medications, kind of circling back towards that question that we've touched on a couple of times, whether medications can be tapered or withdrawn in a staged manner for some patients?
Wilcox: This was a wonderfully done trial that was very rigorous. It was, in fact, tricky to do. Some argued that maybe they shouldn't have done this trial, but I think Brian Halliday and Sanjay Prasad, who were the principal investigators in the trial, did a fantastic job of really monitoring patient safety. No one was injured and everyone had recovery from their heart failure event.
I think we've learned a lot of lessons from TRED-HF. The first is that we just don't have great data about who has truly recovered, and I think this sort of pumped the brakes for those of us who think about recovery versus remission. We all sort of accepted that maybe remission is good enough and that patients... It's no fun to take a lot of medicines and there are side effects. But within 2 months having half the population have a heart failure event or a rise in biomarkers, I think, was a wake-up call for us. We, in fact, should not discontinue any medications for those patients that we see with recovered cardiomyopathy in our clinics and I want to make sure that that point is clear.
But when we're thinking about future trials, I have talked a bit with them about how would we design TRED II. Maybe we need to be looking more at the clinical phenotypes and the genetics of these patients who truly could have a phased withdrawal, not necessarily of all their medicines, but maybe just the MRA, the ACE inhibitor, or just that beta-blocker, whatever they're potentially incurring more side effects from. I think that's in the works and I would be interested to see what that looks like.
Then another question that goes along with that is how long are you going to be in remission from heart failure? How long can we expect that you'll have a favorable response to these medicines? I think that's something that we're actively looking at as well.
Is there a particular population? Not right now. I think the CRT [cardiac resynchronization therapy] population. There was a recent study by -- and I think from Cleveland Clinic -- Wilson Tang and his group that looked at CRT and turning off CRT, or weaning medications and CRT. That may be a population where just the presence of CRT pacing therapy is enough and has normalized the heart enough where we could start to wean medications, but really remains to be seen.
Perry: Is that talking about the "super responders" to CRT?
Wilcox: Correct. People with a very, very wide left bundle branch block and their neurohormonal profile, their ejection fraction, their volume, everything really normalizes in their class I symptoms with CRT pacing therapy and very little medical therapy. I think we all see those patients in our clinic and we're like, "Okay. You have definitely responded favorably to CRT-P. We are not losing this."
Perry: Got it. We've gotten to this point. I want to circle back now to our patient and look at what do we know, and maybe think about what lies in the future for her. She's had improvement of her ejection fraction. It's now normalized and we think she should stay on her medications long-term. But as you had mentioned earlier, she's still at risk for future heart failure events. In specific, do these patients have fewer hospitalizations? Are they still less likely to have LVAD implantations or ICD implantations than our other HFrEF patients who have a persistently low ejection fraction?
Wilcox: Yes. Their clinical profile and their risk is definitely better, or improved, when we compare it to HFrEF populations. However, I think the important message and the conversations that we have with our patients are, "Just because you're recovered or you're now in remission from heart failure doesn't mean that we stop being vigilant and we stop seeing you in clinic, your medications, occasional imaging, biomarkers, watching for any new events in terms of downturn in those markers." We do know that patients are at increased risk when we compare them to a general population, so there's this risk that you have of time spent with reduced ejection fraction heart failure that you can never get away from.
Perry: While their risk is lower than other patients with persistently reduced ejection fraction, they do not have a normalized risk profile in comparison to the general population as a summary?
Wilcox: Correct.
Perry: Okay. Thinking about how to... how do you follow up with these patients? How often are you following up a patient who has a recovered ejection fraction?
Wilcox: This is a very important topic and we are putting together a consensus document to help our community at large. How do we manage these patients? What do we look for? How do we make sure that they stay in remission?
One of the things that we've tried to do is we want to risk stratify this recovered EF patient, because everyone's not the same. A 35-year-old patient who's recovered, we may follow a little bit differently than a 65-year-old patient who's recovered.
When patients do have a drop in their ejection fraction, a new event, rise in biomarkers, we want to be intensifying medical therapy and we also want to look for underlying things. As you mentioned, our 64-yr-old had an angiogram with no coronary disease. But 10 years down the line, if her ejection fraction is 25%, we should be looking for coronary disease at that time.
You're allowed to have new things happen to you and a lot of those things are going to be secondary to our lifestyle and aging -- so coronary disease, atrial fibrillation, hypertension, obesity -- those types of things that may affect our patients with recovered cardiomyopathy.
We look at genetics, just to look at risk over time, again, looking for those bad actor genes, like lamin. I think it's important that these patients aren't lost to follow-up, that they see us every 1 to 2 years, that we check biomarkers, that we do intermittent imaging. Similar again to that patient in oncology clinic who is in remission, but still following up to avoid recrudescent heart failure.
Perry: Got it. Very nice. In thinking of that follow-up, there was another patient that I encountered at the VA who had very similar... at Veteran's. It's a male. He had a dilated cardiomyopathy and then had improvement of his ejection fraction. I think his nadir was like 25% and then he got up to 55%, and had done great for like 10 years.
He also had an ICD implanted and then the time came up for his ICD, for the generator, to be changed. His EF was, I think, still 50% at that point and so they went ahead and did his generator change, never... it was implanted for primary prevention. It had never been used. Then a year or 2 after his generator change, he has a VF [ventricular fibrillation] arrest and his ejection fraction is 45%.
Seeing that case just really highlighted to me, or it raised a lot of questions, first in that it was surprising that there was still this risk for VF arrest with a normalized -- or at this point maybe not totally normalized -- but a much improved ejection fraction, greater than what our guidelines would suggest for the 35% cutoff.
Then also thinking about the time for his generator change and how would you have made that decision? Perhaps somebody may have made a different decision for that patient. What thoughts do you have or comments can you make about this idea of ICDs that are implanted and management for those going forward?
Wilcox: This is a really important area in recovered cardiomyopathy that deserves some more focused research. Our device therapy in the recovered EF patients is really not specifically addressed at all in current guidelines.
There is a recent meta-analysis that supports the notion that there is this persistent arrhythmic risk among recovered EF patients. I think they had about a 3% per year rate of appropriate ICD therapy in among patients whose ejection fraction was greater than 45%.
We also have data from the SCD-HeFT trial. This is retrospective, again, but it looked at those who had improvement in their EF to greater than 35% during follow-up. They actually accrued a similar mortality benefit with an ICD, compared with those whose EF remained less than 35%.
Again, there is this risk of reduced EF and time spent. If you had an indication for an ICD at that time, even though your overall risk may be lower than someone with lot of scar and an EF of 10%, you still accrue a mortality benefit from an ICD, at least in the data that we have.
For my patients, unless they've had some terrible side effect from their ICD, they've got a pocket infection or a lead fracture or whatever, or they're not expected to live 12 months or 13 months or something, whatever they... That discussion, that shared decision-making, I'm really telling them that the best data we have right now supports the generator change. It's definitely an area that's ripe for research because patients don't necessarily want to go through that if they don't have to.
Perry: Totally. I think that covers a lot of the highlights of everything we talked about. We've had a whirlwind and covered really just a gamut of a lot of different topics for these types of patients. Before we close, are there other topics or issues or questions that often come up in your clinic or with consults that you see that you think are important to highlight, or closing remarks?
Wilcox: I think we've covered a fair amount. These are typical questions and a typical patient that I would see in my clinic. I think what I would highlight going forward for trainees and people who are really interested in this space is that patients with dilated cardiomyopathy, even if they've recovered, are still at risk for heart failure. Also, we should be thinking about these patients actually as a family unit and we should be looking at their first-degree relatives -- their brothers, sisters, children -- who may also be at risk for heart failure with reduced ejection fraction or mild dilated cardiomyopathy. Informing those patients that they are at increased risk, they should get an echocardiogram, they should be screened, and they should modify their lifestyle to reduce their risk for heart failure. Really thinking about the family as a unit and moving the needle to preventing heart failure, I think, is going to be the wave of the future.
Perry: Awesome. Very cool. I am very appreciative of the time that you took out to visit with me and have this discussion. I found it very informative.
Wilcox: Thank you so much for having me. It was really fun.
Perry: To summarize a few of the main highlights from today's episode, patients with heart failure and recovered ejection fraction, or HFrecEF -- these comprise of patients who have reduced ejection fraction which then normalizes. They are at reduced risk for future heart failure events, but it's important to realize that they do not have a normal risk compared to the rest of the general population. These patients should be conceptualized in analogous terms to patients with cancer who are in remission.
Rather, these patients are in remission from their heart failure and remain at risk for future events. Thus, these patients at present should continue to remain on their heart failure medications. There was a randomized controlled trial, the TRED-HF trial, which demonstrated that patients who were weaned off their medications were at greater risk with having another heart failure episode.
This is an active area of research and we can expect to learn a lot more about this patient population in the years to come. Thanks again for listening.
is a cardiology fellow at the University of Washington Medical Center in Seattle.