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EP-EDGE brings you the latest in cardiac electrophysiology — from breakthrough research and clinical insights to future-shaping innovations. Hosted by Dr. Niraj Sharma, an electrophysiologist with over 15 years of experience, each episode delivers clear, evidence-based updates designed to inform, inspire, and elevate your practice.
Hello, everyone. Welcome to the fourth edition of EPH August 2025. I'm doctor Niraj Sharma. Today, we'll go in-depth into factor 11 inhibition, which potentially could change the whole anticoagulation landscape. Factor 11 is part of the intrinsic coagulation pathway, and it usually becomes active in a prothrombotic state and has minimal or really no activity during physiologic coagulation.
Dr Niraj Sharma:The whole idea of utilizing factor XI as a target for anticoagulation came from genetic studies in patients who had partial deficiency of factor XI. And it was found in those patients that they had really minimal or no thrombosis, I e, a very low risk for strokes. The data thus far has been mixed. Two trials, the PACIFIC and the OSANIC AF trials, shown significant reduction in dealing, but efficacy remains a little dubious. There are, however, two other trials with two different agents currently underway that may shed more light into factor XI inhibition.
Dr Niraj Sharma:Okay, get ready to deep dive into the August 2025 issue 4A of EP Edge. And as mentioned previously, this is AI narration of my LinkedIn newsletter, Issue 4A, August 2025. Note, this has been personally vetted by me for accuracy. You'll find during this AI presentation that there's some mispronunciation, particularly for factor XI. I hope you'll keep that in mind and excuse me for that discrepancy.
Dr Niraj Sharma:Okay, let's deep dive.
AI 1:Welcome to the deep dive. Today we're, really getting into something cutting edge, factor EVA inhibition. We're looking at how it might change the game for stroke prevention, particularly for people with atrial fibrillation, you know, AF.
AI 2:Yeah. And the core mission here, it's pretty ambitious actually. We're trying to effectively stop those dangerous clots around thromboembolic suppression, but, and this is the key part, decouple that completely from the risk of serious bleeding.
AI 1:Okay. That sounds like the ideal scenario. Almost the holy grail. Right?
AI 2:It really is an anticoagulation.
AI 1:So factor U just specifically. Why that target? We already have pretty effective drugs like the factor Zs inhibitors. What makes this pathway potentially better?
AI 2:Well, it's about the biology, which is, quite distinct. Factor Esia, it really pushes thrombin generation hard, but mainly in prothrombotic situations, disease states like in AF. But crucially, it doesn't seem to play a big role in baseline hemostasis.
AI 1:Baseline hemostasis, maybe break that down a bit for us for those not deep in hematology.
AI 2:Sure, yeah. That's just your body's everyday clotting system. Stopping a paper cut, handling a minor bruise, that kind of thing. Essential stuff.
AI 1:Got it.
AI 2:So the idea is we're targeting the clotting that happens because of the disease, not the clotting your body needs just for, well, for living. Mhmm. And the initial clue, the sort of moment.
AI 1:Yeah.
AI 2:It came from observing people naturally born with low factor ECH. Can have fewer strokes, fewer clots overall, but without a corresponding big increase in bleeding problems.
AI 1:Interesting. So nature kind of provided the proof of concept.
AI 2:Exactly. Yeah. It set the stage perfectly for thinking, okay, maybe we can mimic this pharmacologically.
AI 1:Which leads us to the first big safety test. Abilasumab comes to mind. If that theory holds, you'd expect to see way less compared to what we use now. Did azelitamab seventy one show that?
AI 2:It did, emphatically. Yeah. That trial delivered a really strong safety signal. We saw about a sixty two percent reduction in major or clinically relevant non major bleeding compared to rivaroxaban.
AI 1:Wow, sixty two percent.
AI 2:Yeah, it was dramatic. It basically confirmed the core hypothesis right there.
AI 1:Okay, that's impressive on the safety side. So why aren't these drugs everywhere yet? What happened when they started testing efficacy, you know, actually preventing strokes?
AI 2:Right. And that's, that's where the story gets a bit more nuanced. Just hitting the target doesn't automatically mean it works effectively for the endpoint you want. Meaning? Well, take a Syndaxin.
AI 2:It showed a better bleeding profile, definitely. But then the big oceanic AF trial that got stopped early. Why? Because it turned out it wasn't preventing strokes or systemic embolism as well as apixaban. It was actually inferior on efficacy.
AI 1:So safer bleeding profile but didn't work well enough.
AI 2:Exactly. It really highlights that success isn't guaranteed. It likely depends on the specific drug, maybe the dose, the trial design, lots of factors.
AI 1:Which makes the ongoing trials critical. We're keeping a close eye on abalasumab again in lilac thymi-seventy six. That one's looking at efficacy versus placebo, but specifically in patients who are already at high risk for bleeding.
AI 2:Yes, a very important group. And then there's Milvexian with the Librexia AF trial. That's the big head to head against apixaban.
AI 1:High stakes there. The results from those could really shape the future, couldn't they?
AI 2:Absolutely. If these factor inhibitors do deliver on both safety and efficacy in these trials? Well, the implications are pretty huge.
AI 1:How so? What changes clinically?
AI 2:It could fundamentally change who we can offer anticoagulation to. Think about all the patients right now who we hesitate to put on current drugs because their bleeding risk is just too high.
AI 1:Right, they're left unprotected pharmacologically.
AI 2:Precisely. If these new agents work and are safer, we could potentially bring those patients into the fold, giving them effective protection they can't safely get now.
AI 1:Okay, so it expands eligibility. How does that impact something like left atrial appendage occlusion or LAO? That's the procedure some patients get now if they can't take anticoagulants long term.
AI 2:Good question. LAO's main role today is really for those patients with contraindications to long term drugs. If we certainly have a highly effective pharmacological option with much lower bleeding risk,
AI 1:then LAO becomes less necessary for that group.
AI 2:Potentially. Yeah, its role might become more niche, maybe reserved for very specific anatomical reasons or patients who fail if they using these newer drugs, rather than being the go to for anyone deemed high blood risk, you'll become a more selective strategy.
AI 1:Makes sense. Okay, before we wrap up on AF, let's shift gears for just a second. We often do a quick, actionable insight on these deep dives. Something practical for health? We hear 10,000 steps a day all the time.
AI 1:What's the real story there based on recent research?
AI 2:Yeah, that 10,000 number is everywhere, isn't it? But, a good review, I think it was in The Lancet Public Health looked at this again, and it found that while more steps are generally better, most of the significant risk reduction for major health outcomes, it actually tends to plateau somewhere between 5,007 steps a day.
AI 1:Plateau. So the big gains happen before 10,000?
AI 2:Largely, yes. Getting up to around 7,000 steps a day gives you a huge chunk of the benefit compared to being sedentary.
AI 1:How huge? What kind of numbers are we talking about?
AI 2:Well, to someone doing, say, only 2,000 steps a day, hitting that 7,000 mark was linked to significantly lower risks, something like a forty seven percent lower risk of all cause mortality.
AI 1:Wow, nearly half.
AI 2:Yeah. So that 7,000 steps becomes a much more achievable, realistic target for many people, but still offers substantial health benefits. A good public health message, maybe?
AI 1:Definitely more encouraging than 10,000 for some folks. That's a great takeaway. Okay, back to AF and factor A. Given the mixed results so far, like with Oceanic AF, what keeps this area the next frontier? Why is there still so much hope pinned on it?
AI 2:Because the fundamental promise is still there, and is revolutionary. If these upcoming trials are successful, Factor A inhibition proves you can fundamentally change that risk calculation. You can target the specific pathology, the intrinsic coagulation pathway's role in disease without crippling essential hemostasis.
AI 1:It validates the whole biological concept.
AI 2:Exactly. And that success then opens up a really provocative question for the future, something for you listeners to mull over.
AI 1:Which is?
AI 2:If we can successfully target Factor C this way, what other specific coagulation factors, involved only in particular disease states, could we potentially inhibit selectively down the road? Could we find even more targeted ways to treat clotting disorders without causing bleeding? That's the exciting horizon this research opens up.
Dr Niraj Sharma:Factor XI inhibition has great promise and unfortunately we'll have to wait till October 2026 for the meldexian Lilac TIMI-seventy six trial and then May 2027 for the abalizumab Librexia trial. If these trials are positive for both reduced bleeding and decreased risk for stroke, you can imagine how disruptive in a good way these trials would be. Thank you again for joining me on this episode of EPH. If you need data source and infographics, this can be found in my LinkedIn newsletter. I'd love to hear from you.
Dr Niraj Sharma:You can email me at EPEdgeCast@gmail or via LinkedIn. This is Doctor. Niraj Sharma. Bye for now.