I'd like to welcome you to this episode of The Lead, coming to you live from HRX in Atlanta. This episode is brought to you by the Digital Education Committee from the Heart Rhythm Society. I have with me here today Professor Prash Sandesh from the University of Adelaide and Chris Chung from the University of Toronto. I'm Melissa Middeldorp from the University Medical Center of Groningen in the Netherlands. And today we're going to discuss the recently published Ascendexion versus Epixaban in patients with atrial fibrillation, and this is the OCEANIC trial. I'm going to hand over to my colleague Prash Sandesh to discuss this study. Thank you. Thanks, Melissa. So this was presented at the ESC Congress earlier this week, and this is Ascendexion, which is an activated Factor XI inhibitor versus Epixaban, and it was a study that was sponsored by Bayer. Now this was based on the PACIFIC trial, which really looked at dose testing to identify the dose that was used, and they compared 50 milligrams of Ascendexion versus appropriate dosing of Epixaban twice a day. Something specific about this drug, it's a 16 to 18-hour half-life, and less than 15 percent of it is renally cleared. The premise of the study is that they had already shown in PACIFIC that safety was better. There was less bleeding associated with that. So in this study, they were really looking at how that altered efficacy in patients with atrial fibrillation. So the idea was to use an event-driven powering to allow the identification of a superiority in terms of events of preventing stroke or a systemic embolism in this population of patients. And as a secondary endpoint, it was a safety endpoint of trying to look for bleeding risk associated with this. This was a phase three international double-blinded study, and it was done in 38 countries and had 1,035 sites, so quite a big study. They did avoid the use of non-steroidal anti-inflammatories, but patients were allowed to be on aspirin if they needed to. Now the study was, in fact, stopped early. And it was stopped at a recruitment of 14,810 patients, and this was stopped by the DSMB. And it was stopped largely because of a safety concern in terms of the efficacy associated with the intervention arm. So the population itself that was in this, there were 73 years of age on average. They interestingly had 27% of patients of Asian background, which was kind of important because studies have not had that before. And they were quite geographically diverse. Most continents were included. Africa was not on this. And they had significant comorbidities with a CHADS-VASc score of 4.3. So this is a reasonable population to look at. Now one of the things that was notable is that 1.6% and 1.8% of the groups respectively, it was their new onset of atrial fibrillation. And then 37% and 36% were paroxysmal atrial fibrillation. And this may come up in the discussion later on. Now in terms of stroke and systemic embolism, what they found was the intervention group had 1.3% incidence compared to a PIXABAN, which had 0.4%. And this is what led to the trial being stopped. They also found that the composite endpoint of myocardial infarction, stroke, or death from cardiovascular disease was higher in the intervention arm, 2.1% versus 1%, again significant with a hazard ratio of 2.02. And the rate of bleeding, as they found with PACIFIC, was significantly lower, 0.2% versus 0.7%. And so they're the hard facts about the study. And I'll hand over to Chris to talk about some of the limitations. Thanks Prashanth. And thanks for the opportunity to be here today. It's very exciting to see these results and very interesting. I think a lot of us had expected these results coming down the line already, given that we had heard that OCEANIC-AF had terminated early, I think back in November. We were already expecting that these potentially would be negative results. And what the reason was, was I think up to speculation, but many suspected that it could have been resulted in related to higher stroke and systemic embolism rates. I think this is an important study and certainly really highlights the need for randomized clinical trials in this space. There's certainly been a lot of promise with factor and levonate inhibitors over the years. I think there was a lot of excitement going into this with Pacific AF, as you mentioned that 11As may find this sweet spot of reducing the concerns for bleeding while achieving the same efficacy with stroke prevention. And certainly that's where a lot of the excitement came for these factor 11A inhibitors. And still we know that there are many patients that don't receive appropriate or at least appropriate right dose anticoagulation perhaps due to concerns for bleeding or many patients that may not even receive anticoagulation due to concerns of bleeding. And that's where these factor 11As provide so much promise. So it is in some ways sad to see these results, but it's also important and highlights the need for randomized trials to really rigorously evaluate these new agents that we're evaluating. I think in terms of potential limitations or considerations when we look at this study, a few things come to mind. Of course, the dose that they studied was 50 milligrams of the atzindexan and one of the comments was the correct dose to study. And as you mentioned earlier, the initial study, Pacific AF, was a dose finding study where they looked at 20 milligrams and 50 milligrams. And they did show that 50 milligrams of the atzindexan achieved about 92% to 94% reduction in the factor 11A levels or activity levels. But certainly one wonders, do we need more than 94% or do we need closer to 99%? So that's certainly one consideration. And I think it's also important to highlight that just because this study is negative doesn't mean that other studies in the factor 11A space still may have a lot of potential. And we know that from studies like Azalea Timmy with the monoclonal antibody to inhibit factor 11A, there is still certainly a lot of promise in those studies. So that's certainly an important consideration. And lastly, as you mentioned earlier, this study was terminated early. And so considerations for a termination study termination early potentially leading to over-exaggeration of the termination results. I think one of the other things that I'd raise in this is the point that the discussant on the day raised as well, that was Elaine Eilich when this was being presented, is that there seemed to be a disproportionate number of paroxysmal AF patients in this population. So first onset paroxysmal AF, I mean, you're talking about 38% of each group being in that category. And she also raised that the actual methodology required just a single ECG over the last 12 months, which suggests that the burden may be lower and may be reflected by the fact that the epixaban group actually had lower incidence of stroke or embolic event compared to what we've seen from prior studies. So I think that may have contributed to this result as well. So I think that needs to be considered. So you think that they're potentially recruiting a lower-risk cohort of patients for the study? So perhaps the study needs to have a higher-risk cohort of patients? So that's an interesting point. So if you look at the comorbidities that are described in the baseline characteristics, they're actually quite a sick group of people that we're dealing with here. They had significant, and if you look at the CHADS-VASc score, it's four. So that's significant. But we're starting to realize AF burden has a significant role in terms of stroke risk as well. And perhaps we haven't quite dwelled into that as much as we need to. Yeah. I mean, they were talking about doing sub-analysis. And so I think it'll be interesting to see when the sub-analysis comes out of these patients that came in, like the naive patients. They talked about this a lot as well, the anticoagulation-naive patients that were recruited. What were the subgroups of these patients? And who were the at-risk patients? And who were the low-risk and high-risk patients? So I think we need to do further analyses on this cohort to get a better understanding of who's being recruited into these studies. What do you think some of the key things we've learned from this study is? And where do we go from here? So I guess if I was looking at the data relating to this drug, it's mainly been in venous thrombosis. And it's been very, very positive. Okay? Now, one presumes it's the same thrombogenic milieu that's causing AF-related strokes. But perhaps we need to be aware that there may be other mechanisms involved as well. I want to give a real big shout-out to the one fact that they had so many Asians that were recruited in this study. You know, this is a population that notoriously feels that they are overdosed on anticoagulants and they have a higher risk of stroke. And 27% of both groups, that's an incredible finding. And I suspect it would be interesting to see what the sub-analysis does in that sort of population here. And certainly a lesson in clinical trial design, right? Making sure that you have a broad and diverse population that captures everyone that could potentially be needing this type of drug and so that it can be generalizable to the population at large. And so that's very important. And I want to focus on an earlier point. You're right that there are still ongoing studies like oceanic stroke that are looking at acindesion in the stroke population versus placebo. So there are still, you know, there's still potential and there's certainly still consideration for this agent. Yeah. So do you have any further comments on the study? No. I think we've discussed that. Yep. So thank you for joining us today on this episode of The Lead. Thank you.

OCEANIC trial

atrial fibrillation

Factor XI inhibitor

anticoagulation therapies

clinical trials