The AF is Gone, the EF Is Up. Can You Stop the HF Meds?

This transcript has been edited for clarity. 
Ileana L. Piña, MD, MPH: Hello and welcome to the European Society of Cardiology (ESC) meeting in London. My name is Ileana Piña. I am the chief of quality for the cardiovascular line at Thomas Jefferson University. 
Joining me today is the team from Melbourne, Australia, who have been doing some work that really fascinates me because I’m trying to do that as well, which is reversely remodel the heart. 
I’m going to let you introduce yourselves. Dr Prabhu, begin. 
Sandeep Prabhu, MBBS, LLB, PhD: Thank you very much. My name is Sandeep Prabhu, a cardiologist and electrophysiologist, and senior research fellow at the Baker Institute, Melbourne, Victoria. 
Louise A. Segan, MBBS, MPH: My name is Dr Louise Segan. I’m a cardiologist and PhD candidate at the Alfred Hospital and the Baker Heart and Diabetes Institute. My main thesis in my PhD focuses on the atrial fibrillation (AF) and heart failure population. 
Piña: How did you get interested in this? 
Prabhu: We published, in 2017, the CAMERA-MRI study, where we specifically tried to find those patients who did the best with catheter ablation as a treatment for AF and heart failure.
We looked at the group, particularly those without ventricular scar, and realized that many of these patients had underappreciated AF-driven cardiomyopathy. These patients had dramatic improvements in their ejection fraction after restoration of sinus rhythm. Many of those patients, at the end of having fully recovered their ejection fraction, were left on many of their heart failure medications, which were guideline recommended at the time. 
Piña: They were afraid to stop them.
Prabhu: Exactly, particularly drugs like beta-blockers, which you think may have a bit of an antiarrhythmic role, but these patients had no other structural heart disease. They had fully recovered their ejection fraction. 
We thought perhaps in these patients the priority of their management really should be rhythm control rather than necessarily these drugs. These patients are generally fairly young, so they have potentially committed to these medications for decades. That’s a large cost on patients and on healthcare. 
Piña: The burden of the pills. 
Prabhu: There’s a psychological aspect of taking a pill every day. It makes you feel like a patient, and you feel you’re in that model of being a patient for the rest of your life. We thought that these patients, the majority of whom had catheter ablation, perhaps their heart failure is different from standard heart failures that we see around the world, in which evidence suggests that in unselected patients withdrawing heart failure can be problematic and will lead to recurrences.
We thought this group of patients is different, and we wanted to specifically look at them in a very controlled and systematic way of withdrawing therapy while keeping a close eye on their rhythm and their ejection fraction with the benefit of MRI, which gave us a large amount of structural data.
Piña: It’s a different tool. I’ve been looking at the list of the causes of heart failure in this particular population. Somewhere at the bottom was tachycardia-induced cardiomyopathy, and we weren’t paying much attention to it. 
You know, we went through AF, do we want to have rhythm control? Do we want to have rate control? We’ve been through this, yet if you go into a laboratory, how do you get heart failure in a dog? You pace them and they go into heart failure. 
Now, with my own patients, I’ve been checking more often, is it the AF that they presented with, and what happened first? Did the heart go bad and then they develop AF, or vice versa? 
Prabhu: Yeah. I think that was one of the questions we had with CAMERA-MRI, which was the chicken-and-egg question.
We thought the MRI might be the clue, like the presence of scar. Did that give us a clue as to whether these patients had heart failure and developed AF, or did these patients co-present with AF and heart failure at the same time? They tend to be the ones that have this AF-mediated cardiomyopathy and quite dramatically improve just with rhythm control.
Piña: Tell me about how you structured the WITHDRAW-AF study. 
Segan: This is a study that was conducted over 3 years. We started the study in mid-2021. 
Piña: In the middle of the pandemic. That’s very brave.
Segan: That’s right. It’s really challenging because it’s obviously a resource-intensive study. The 60 patients had three MRIs over 12 months, three echocardiograms, and three cardiopulmonary exercise tests. 
Piña: Who paid for all that?
Segan: We’re very fortunate to have had some institutional support and governmental research funding. 
Piña: It’s the only way you can do this. 
Segan: It was really important because we felt the quality control for a study such as this, where it’s such an important safety consideration, required us to really judiciously monitor these patients.
The study was conducted with a double-crossover design. Basically, we randomized 60 patients, 30 to initial medication withdrawal and 30 to continued medical therapy initially, followed by subsequent withdrawal at 6 months. The reason for that design is to ensure that each patient acts as their own control.
They were off their medication for 6 months. Medication weaning occurred up to 12 weeks, and then the timing from being off therapy to reassessment was a further 6 months to make sure we really had an adequate amount of time to reassess for whether the left ventricular ejection fraction changed.
Piña: Then you flipped them.
Segan: That’s right. That’s maybe controversial, but we wanted to make sure. 
Piña: I don’t think so. I like crossover designs. I think they’re solid. 
Segan: What was interesting is among the people who did cross over, not all of them were able to get back up to the doses that they were on before. That shows really that issue around tolerability of these drugs. It is really important that, in these patients who had previously been on high doses, they may not have tolerated reintroduction at the same level. 
Piña: We’ve always thought that when you take patients off the drugs because they’re very sick, it’s very hard to get them back on it. I’ve only done that in the really sick.
You kept this up for 6 months? 
Segan: Six months on the medication and 6 months off the medication. It’s a 12-month study follow-up period. We’re very pleased to say that no patients were lost to follow-up in the study period.
At the end of 12 months, individuals who were able to maintain their ejection fraction off the heart failure drug therapy were invited to continue in a longer-term prespecified analysis, where they continued off their therapy for a further 12 months with an echocardiogram thereafter to assess the long-term durability of the results.
Piña: That’s really interesting. What did you do about blood pressure? What if the patient had a hypertensive etiology for their dilated cardiomyopathy? 
Segan: That’s a really important question. You might note that, in this study, very few had a preexisting diagnosis of hypertension. I think that just reflects how highly selected this population was. We intended it to be that way because we wanted to make sure we’re not introducing confounding from other etiologies as contributors to heart failure. Very few had preexisting hypertension. 
Across the study, after medication withdrawal, we did see a rise in systolic and diastolic blood pressure. It was significant in some patients, and the study protocol was designed so that we could initiate blood pressure–lowering therapy. We specified that would be a peripherally acting calcium-channel blocker during the period of withdrawal. 
Piña: Right, to get them out of the renin-angiotensin cascade. Because then they’ll go back into AF with the high blood pressure and get into that cycle again.
Segan: That’s right. In the longer term, there was a subset who had to go back on some of these agents, not for heart failure but because of the development of systemic hypertension. 
Piña: What did you find? 
Segan: The primary outcome was actually maintenance of left ventricular ejection fraction (LVEF) ≥ 50% following medication cessation compared with medical therapy. This is a hard analysis to account for because we expect that in those continuing medical therapy, you won’t have any relapses, as has been shown in TRED-HF. 
The way that we conducted the analysis was using binary logistic regression. On the basis of that, we found there was no significant difference with respect to the primary endpoint in LVEF maintenance between medication cessation versus medication continuation at 6 months. 
Then we looked at a number of secondary endpoints, so things such as cardiac parameters, both volumes and function, left atrial size, functional parameters, so VO2 max, 6-minute walk distance, and biomarkers of heart failure. Again, we found no significant difference in any of those on vs off heart failure therapy
Piña: Did you look at N-terminal prohormone of brain natriuretic peptide (NT-proBNP)?
Segan: One thing we did see, which was interesting, is that left atrial size continued to reduce, This showed that these patients exhibit ongoing reverse remodeling in the atrium, which we know is prognostically important in these patients.
Piña: We don’t look at the atria as much when we look at reverse remodeling. I look at mass and I look at left ventricular end diastolic and end systolic volume index. 
Prabhu: In some ways, we think that it’s the sinus rhythm that’s the ongoing driver. 
Piña: In the European guidelines, they talk about opportunistic testing. Do you get periodic Holter monitors to see whether they’re having bouts of AF? 
Segan: In this study, we felt that more continuous remote rhythm monitoring was required because we’re assuming that AF is a major factor in relapse of cardiac dysfunction. Some patients had indwelling devices. That would include either defibrillators or pacemakers. A few patients had loop recorders. Then the remaining patients had AliveCor devices, where they would send a minimum of two recordings a day or additional recordings for symptoms. 
Piña: At home. 
Prabhu: Yes, that can be just done through their phone or their iWatch. 
Piña: So you do believe in opportunistic screening.
Prabhu: Yes, absolutely. For these patients, rhythm control is key. Many of these patients, when they present with their heart, they don’t present with palpitations. Often, they co-present once the heart failure symptoms take over.
Picking up early when they get recurrence of AF is really important. I think it’s important for all these heart failure patients who have AF. 
Piña: What do you do with anticoagulation? 
Segan: That’s a really good question. It came up in the session earlier today. The study protocol wasn’t designed to withdraw anticoagulation in these patients. 
Piña: You kept them on it. 
Segan: We kept them on it. Interestingly, 58 out of 60 were on anticoagulation. The remaining two were actually not anticoagulated at the time, which was based on treating physician discretion. 
What’s really hard, and I think the literature fails to tell us, is what to do in patients who were a CHA2DS2-VA of 1 based on heart failure alone, they’re young otherwise, and now their heart failure is essentially reversed. Are they now a CHA2DS2-VA of 1 or 0? What do we now do about their anticoagulation? I think that’s still an unmet question in the literature that we need to answer. 
Piña: We have a history of that with the AFFIRM trial, originally, which you would know. 
Prabhu: Yeah. 
Piña: Some people came off, it was warfarin at the time. They came off warfarin, and we found strokes subsequently. That, I think, makes us a little nervous. 
Segan: The other thing that’s difficult in these patients is, as Sandeep said, because they’re often not symptomatic with AF, we have to really closely monitor them because otherwise they could have thromboembolic complications. 
Piña: I have many patients who do not feel it. 
Prabhu: I tell patients that the anticoagulation is sort of their insurance policy against stroke. It doesn’t make them feel any better. Really, one of the worst outcomes of AF is stroke. 
Piña: It would be absolutely terrible. 
Prabhu: It’s the worst way to have your AF diagnosed.
Piña: I encourage the audience to get your patients well medicated because there is a possibility [of reverse remodeling], especially in the younger ones, the ones who haven’t had heart failure for a long time, and perhaps the ones who have no fibrosis on an MRI. These people deserve to have the best of the drugs, and in good doses, and see if you can reverse them.
I want to thank you for being with me today. This is a fascinating study. Congratulations. To my audience, thank you for joining me today from the ESC. I bid you farewell.
Ileana L. Piña, MD, MPH, is a heart failure and cardiac transplantation expert. She serves as an advisor/consultant to the FDA’s Center for Devices and Radiological Health and has been a volunteer for the American Heart Association since 1982. Originally from Havana, Cuba, she is passionate about enrolling more women and minorities in clinical trials. She also enjoys cooking and taking spin classes.