Dr. Harriette Van Spall:
"I'm Harriette Van Spall, clinical trialist, from Canada and I'm delighted to have with me my dear friend Dr. Maja Cikes, a clinical trialist from Croatia. And we are here at HFA 2025 to discuss some of the late breaking clinical trials. Welcome Maja.

Dr. Maja Cikes:
Thank you so much Harriette, for having me. It's really a pleasure.

Dr. Harriette Van Spall:
So this has been a meeting in which many of the trials have been secondary analyses of some of the larger industry sponsored interventions. And then we've had some small investigator initiated trials, so maybe I'll start off with one of the latter. There was a small single centre trial of around 100 patients that I thought was interesting and potentially clinically relevant. It was a trial in which patients with heart failure and reduced ejection fraction who were on stable medical therapies, and excluded patients who were recently hospitalised were randomised to either continued diuretic therapy or withdrawal of diuretics as long as they were not congested. And I thought that the relevance of the study is that it highlighted that we may sometimes be using diuretics inappropriately in these patients to the folly of titrating GDMT potentially. The intervention withdrew the diuretic therapies from patients randomised to that group and showed that there was no difference in the patient's perception of dyspnea nor in any of the congestion scores or heart failure events. And it was a short open label study with some limitations but I thought it merited further investigation. Potentially a multi centre trial. There were some details that were not clear but I thought that that was a interesting clinically relevant study. What, what about you? What did you think?

Dr. Maja Cikes:
That's a very interesting point to highlight and of course we're always enthusiastic about investigator initiated trials and hoping for them to be hypothesis generating for larger prospective randomised trials where we can learn more about these interesting concepts that are set forward. And thank you for highlighting that Harriet. In terms of secondary analyses that we have seen being presented at this meeting, I'd like to highlight, one presented that has been presented from the FINEARTS trial that in fact specifically addressed patients that were recently hospitalised for heart failure. Such a vulnerable population of patients, we know that there is a high risk of rehospitalization, even high risk of death soon after a heart failure hospitalisation event. And in fact in FINEARTS, this subanalysis looked into the patients that were randomised to the trial either while still hospitalised for this event or within the next Seven days. So patients very, very acutely after, very soon after this important event. And of course as in the trial, the patients were randomised to finerenone or placebo. And what this subanalysis has shown, and it was focused on heart failure events happening soon thereafter. So between one month and three months, is that those patients randomised to funerenone had a lower risk associated with a recurrent heart failure event in the soon period thereafter. So I think really interesting data in this high risk population and hopefully ways how we can protect our patients even better.

Dr. Harriette Van Spall:
Right. And consistent with the findings of the larger trial which absolutely demonstrated efficacy of finerenone in heart failure with mildly reduced or preserved ejection fraction, there was another secondary analysis from this trial that demonstrated that blinded withdrawal of patients at the end of the intervention period was associated with increased risk, interestingly increased risk in both the placebo group that had received the placebo but then had it withdrawn and the finerenone group. The finerenone group sustained a higher risk relative to when patients were receiving the therapy than the placebo group. And so the findings were consistent with other trials that have demonstrated the risk of withdrawing therapies from patients who have heart failure. We've seen that both in the TREAD HF trial that tested the hypothesis systematically across GDMT groups, but also in some sub analyses of the SGLT2 inhibitor trials. So EMPEROR, for example, that the risk of withdrawing therapy was not benign. So it reminds us as clinicians to continue therapies even when patients feel stable. Because otherwise we put them at an increased risk by withdrawing those therapies.
Dr. Maja Cikes:
Exactly. That's a great point. It's so important to remember this across the ejection fraction spectrum.

Dr. Harriette Van Spall:
Right, right. Because so often we talk about heart failure with improved ejection fraction that occurs once we start treating patients with GDMT for heart failure with reduced ejection fraction. But clearly a concept we need to bear in mind also in our patients with heart failure with mildly reduced or preserved ejection fraction as well.

Dr. Maja Cikes:
Great. And gives us more data. Now when patients ask to have therapies deprescribed that we can show them the evidence to support why they should be on therapies.

Dr. Harriette Van Spall:
You were going to tell me about an interesting ATTR, intervention and we started talking about that before this recording. So maybe share some of those results with us now.

Dr. Maja Cikes:
Yes, we've seen some interesting data, specifically again focusing on ATTR amyloidosis shared at at this meeting I think of course a very intriguing, interesting promising therapy is CRISPR CAS genetic gene editing for this disease. And it has been shown already previously that this approach leads to lower concentrations of TTR and activity of TTR in patients with the disease. But what we have learned also at this meeting is that the CRISPR gene editing approach is equally effective both in patients with the hereditary and those with the non hereditary form of TTR amyloidosis. So promising results for even a broader population of patients.

Dr. Harriette Van Spall:
Absolutely. And that field has really comes along by leaps and bounds showing that there are various strategies to treating people with cardiac amyloidomae. A few years ago when we were earlier on in our careers there were no treatment really. So this has been the era of leaps and bounds in cardiac amyloid therapy. A related trial looked at the longer term outcomes of vutrisiran. We know that this drug RNAi reduced all cause mortality and cardiovascular endpoints in the primary analysis and the analysis presented this weekend was one at a 42 month endpoint or time frame and it demonstrated a reduction in an array of cardiovascular endpoints including heart failure hospitalisation, cardiovascular hospitalisation, worsening heart failure events at 42 months. So remarkable benefits through long term follow up in this high risk group of patients. Another highlight of this meeting. Absolutely. And so valuable to this patient group as well. We should probably touch upon devices.

Dr. Maja Cikes:
Good point, good point. We need to remember that of course it's a very important part of heart failure therapies and perhaps we could mention the RESHAPE trial that addressed patients with grade three to four mitral regurgitation that were randomised to receive the mitraclip procedure on top of of course we should always remember GDMT for heart failure which is so relevant for, for all of our patients uniquely. And I think it's interesting to see how clinical trials are shifting from hard outcomes such as cardiovascular outcomes, cardiovascular survival, cardiovascular death and heart failure hospitalizations. But also the importance of patient related and patient reported outcomes in terms of how they feel with the disease that they have. That said the RESHAPE trial, sub analysis of the RESHAPE trial that has been shared with the community here at ESC HFA was in fact looking specifically at the Kansas City questionnaire and different components of that that would inform us in general about the well being and the feelings and the symptoms that our patients are experiencing with the disease. What was shown as this conference was a follow up of the Kansas City questionnaires, And different aspects of that where patients randomised to receive the mitraclip in fact had superior outcomes in terms of better results of these questionnaires compared to those receiving only GDMT.

Dr. Harriette Van Spall:
Perhaps I'll end with a little innovation that was presented the IVC filter. We often talk about volume and pressure overload and heart failure and sometimes we conflate the two but of course volume isn't pressure. Pressure is not necessarily volume. This single arm trial demonstrated that an IVC filter implanted below the hepatic was safe and was reliable at assessing volume status in patients. And so it potentially gives basis for a phase three trial that could assess the effect that such an intervention has on optimising medical therapy and perhaps we'll end on that note, innovation bridged with known efficacious interventions that we have learned have had secondary endpoints and secondary analyses to further solidify the evidence around their uptake. Thank you so much for joining me Maja.

Dr. Maja Cikes:
Thank you very much, Harriette.