Atrial Fibrillation Ablation in Patients With End-Stage Heart Failure: The CASTLE-HTx Trial Rationale and Design

© 2023 HMP Global. All Rights Reserved.

Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of EP Lab Digest or HMP Global, their employees, and affiliates. 

Featured is the presentation entitled “AF Ablation in Patients With End-Stage HF: The CASTLE-HTx Trial Rationale and Design” from Session 1 of WAFib 2023.

Thank you very much for the introduction and thank you very much for the invitation. I think before we listen to the king's speech, we need to build up another castle, and this is a new castle coming up on the horizon. We need to address the question whether we can really build a castle inside the end zone of heart failure. Therefore, we will discuss this in the next 10 minutes. We know already and we can spend some time on how atrial fibrillation and left ventricular dysfunction belong together. We see many patients in our clinics having heart failure and atrial fibrillation. We still have the question: what is the chicken and what is the egg, and how can we target these different entities and sources of atrial fibrillation? CASTLE-AF was the first study demonstrating benefits in heart failure patients, then came other studies, but it's more or less very clear that we have very good studies showing that the heart failure of endpoints, death, hospitalization, survival are definitely effective in patients when they underwent catheter ablation. We do know this from the CASTLE data and we have presented it several times. Other major trials also confirm that early rhythm control and early catheter ablation and early strategies are very beneficial for heart failure patients. The question is still, why is it so beneficial? We have data also from a CASTLE-AF subanalysis where we checked the ejection fraction, and there is other data coming very soon demonstrating that patients with lower ejection fraction and with a higher degree of left ventricular dysfunction benefit in terms of reverse remodeling. In CASTLE, it was about 8%, a little bit more remodeling in patients with chronic forms of atrial fibrillation. We also observed the patients develop more than 5% ejection fraction after ablation and some patients even achieve a left ventricular ejection fraction higher than 35%. That was very important information. More information came from the DECAAF-II trial. Mario Mekhael will present later, but he published this very nice paper a couple of weeks ago where you can clearly see really reduced ejection fraction in those patients. They had a 16.6% improvement after catheter ablation, and this was independent of the atrial cardiomyopathy stage. I think that highlights again that every patient with reduced ejection fraction and atrial fibrillation should undergo catheter ablation as soon as possible. Another question and another target might be the AFib burden. We will discuss this later on, and we also have data for CASTLE demonstrating that ablation and only ablation can reduce the AFib burden by 50%. We discussed this already a couple of years ago, and you can clearly see that after ablation here on the right side, the AFib burden is very low in these patients. So, a couple of things are important. We needed a translation or a reverse translation of the CASTLE results, keeping in mind the AFib burden, which was really another marker. We published this with Johannes Brachmann a couple of years ago. The AFib burden reduction of 50% is really a mortality benefit. Thomas Körtl did this work. He took the iPSc cells and cardiomyocytes, and stimulated them with different AFib burdens in terms of a reverse translation. As you can clearly see, the action potential was longer when they achieved this 50% AFib burden reduction, and this was also clear for the transient amplitude for the contractility of the heart, highlighting again that the reduction of the AFib burden might be the most important target in heart failure patients. So, when we talk about transplantation, I think it's really also very problematic in the United States. This is data from Bad Oeynhausen on the very left side. We run the biggest heart transplantation program in Europe, and you can see we transplant 60-90 hearts per year. In addition, when we looked back to CASTLE, we see that the exclusion criteria in CASTLE was patients who were listed or eligible for heart transplantations, 224 patients dropped out during the screening or run-in period. When we look at all the other trials, we have no evidence for these patients. It's not clear. Should we ablate early? Should we not ablate? Many drugs failed. Devices failed. So, what can we really do with these patients? As you see, in Germany, they transplant 360 hearts, which is nothing. One out of 10 patients receive a heart. Therefore, I think it's very important when we can delay the time to transplantation, the time to treatment, the time until death in these patients. I think that when we really can go into the end zone, and this is the target for the CASTLE-HTx study, then we can really achieve at least quality of life or at least longer life for these patients. It's still a question of what is the endpoint or what is the inclusion criteria, eligibility, and listing, as every country has different listing criteria. We took the International Society of Heart Lung Transplantation criteria for these patients. So, it was very clear that they were able to undergo or receive a new heart. That was the inclusion. Then, we took more or less the same design as we did in CASTLE already. The study has a composite endpoint death, VAD therapy, or transplantation. It's a single-center randomized trial, and it's powered for 194 patients. I did a poll last week as you see. Is it useful to improve quality of life? Is it too late? Will it improve survival? What is the benefit? It's not clear from the data we have. I'm quite interested in discussing this with you maybe in 1 year when we have more data. We enrolled all the patients over a period of 2 years, starting in November 2020 in the COVID area. You can clearly see that we see a lot of patients in our hospital and different clinics, cardiology, heart failure, cardiovascular surgery, and EP. In May 2022, we included the last patient and we considered a follow-up period of 3 years, having the possibility to terminate the study when the last patient has 1-year follow-up, and this would be in May. The data is very clear. So, we're looking forward to maybe be able to present this as a late-breaker at the upcoming ESC, depending on the numbers. But I'm quite sure that when we do this in 1 year again, you might vote differently. So yes, what we're aiming for at the end of the day is again, we need personalized paths for this cohort of patients where we have no evidence-based medicine, taking the patient into focus, genetics, and mobile health risk factors. We need good imaging. We need good risk stratification for these patients as well. Then, we need to decide whether we should go for ablation in the majority of patients, considering other drugs, maybe also go to high urgent listing in these patients when there is no other option for them. I think at the end of the day, we also need personalized paths for them. So, my conclusion before I give the stage over to the king is that, and I think there's no doubt anymore, the major trials demonstrated that AFib ablation improves the symptoms, quality of life, and heart failure outcomes in heart failure patients, ablate early to avoid left ventricular dysfunction, and allow for mechanical and electrical remodeling, AFib burden, and the ejection fraction. Take this into consideration. We can definitely decrease AFib burden, but only with ablation. Therefore, I think even in this cohort, which is a very complex, very sick, almost close-to-death patient cohort, ablation will also be beneficial in them, and this is what CASTLE-HTx should prove. Thank you very much.

The transcripts have been edited for clarity and length.