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Addressing Suboptimal Anticoagulation in Atrial Fibrillation: Uncoupling the Potential of Factor XI/XIa Inhibition for Stroke Prevention

  • Authors: Marc S. Sabatine, MD, MPH; Jeffrey I. Weitz, MD, FRCP(C), FACP, FCCP; Christian T. Ruff, MD, MPH
  • CME / ABIM MOC / CE Released: 11/17/2023
  • Valid for credit through: 11/17/2024, 11:59 PM EST
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    IPCE - 0.50 Interprofessional Continuing Education (IPCE) credit

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Target Audience and Goal Statement

This activity is intended for cardiologists, primary care providers, emergency medicine physicians, hematologists, nurses/nurse practitioners (NPs), physician assistants (PAs), pharmacists, and other health care professionals (HCPs) who care for patients with atrial fibrillation (AF).

The goal of this activity is for learners to be better able to identify trends and gaps in optimal stroke prevention in high-risk patients with AF, including the proportion of patients with AF who are not optimally treated (ie, undertreated, not treated, and/or mistreated), factors affecting suboptimal treatment, and evaluate the emerging role of factor XI/XIa inhibition for stroke prevention in patients with AF to address current limitations of standard of care (SOC) anticoagulation approaches.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Unmet treatment needs associated with achieving optimal stroke prevention with anticoagulation for patients with AF at risk of stroke
    • Role of factor XI/XIa inhibition for stroke prophylaxis in patients with AF to address current gaps in optimal anticoagulation
    • Emerging clinical trial evidence for the use of factor XI/XIa inhibition for stroke prevention in patients with AF
  • Demonstrate greater confidence in their ability to
    • Discern the value of emerging anticoagulation strategies targeting factor XI/XIa for stroke prevention in patients with AF as part of the interprofessional team 


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  • Marc S. Sabatine, MD, MPH

    Chairman, TIMI Study Group 
    Lewis Dexter, MD
    Distinguished Chair in Cardiovascular Medicine
    Professor of Medicine
    Harvard Medical School
    Boston, Massachusetts, United States


    Marc S. Sabatine, MD, MPH, has the following relevant financial relationships: 
    Consultant or advisor for: Amgen Inc.; Anthos Therapeutics; AstraZeneca; Beren Therapeutics; Boehringer Ingelheim Pharmaceuticals, Inc.; Dr. Reddy’s Laboratories; FibroGen, Inc.; Intarcia Therapeutics, Inc.; Merck; Moderna, Inc.; Novo Nordisk; Precision BioSciences; Silence Therapeutics
    Research funding from: Abbott; Amgen Inc.; Anthos Therapeutics; ARCA Biopharma Inc.; AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Daiichi Sankyo, Inc.; Eisai Inc.; Intarcia Therapeutics, Inc.; Ionis Pharmaceuticals; Janssen Research and Development, LLC; Merck; Novartis; Pfizer, Inc.; Regeneron Pharmaceuticals, Inc.; Roche; Siemens Healthcare Diagnostics Inc.; Softcell Medical Limited; Zora Biosciences


  • Jeffrey I. Weitz, MD, FRCP(C), FACP, FCCP

    Professor of Medicine and Biochemistry
    McMaster University
    Hamilton, Ontario, Canada


    Jeffrey I. Weitz, MD, FRCP(C), FACP, FCCP, has no relevant financial relationships.

  • Christian T. Ruff, MD, MPH

    Associate Professor of Medicine
    Harvard Medical School
    Director of General Cardiology
    Brigham and Women's Hospital
    Senior Investigator, TIMI Study Group
    Boston, Massachusetts, United States


    Christian T. Ruff, MD, MPH, has the following relevant financial relationships: 
    Consultant or advisor for: Anthos Therapeutics; Bayer; Bristol Myers Squibb Company; Daiichi Sankyo, Inc.; Janssen Biotech, Inc.; Pfizer, Inc.
    Research funding from: Anthos Therapeutics; AstraZeneca; Daiichi Sankyo, Inc.; Janssen Biotech, Inc.; Novartis


  • Asha P. Gupta, PharmD, RPh

    Medical Education Director, Medscape, LLC 


    Asha P. Gupta, PharmD, RPh, has no relevant financial relationships.

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  • Maria Morales, MSN, RN, CLNC

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Maria Morales, MSN, RN, CLNC, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Addressing Suboptimal Anticoagulation in Atrial Fibrillation: Uncoupling the Potential of Factor XI/XIa Inhibition for Stroke Prevention

Authors: Marc S. Sabatine, MD, MPH; Jeffrey I. Weitz, MD, FRCP(C), FACP, FCCP; Christian T. Ruff, MD, MPHFaculty and Disclosures

CME / ABIM MOC / CE Released: 11/17/2023

Valid for credit through: 11/17/2024, 11:59 PM EST


Activity Transcript

Marc S. Sabatine, MD, MPH: Hello, I'm Marc Sabatine, Chair of the TIMI Study Group and professor of medicine at Harvard Medical School. Welcome to the program titled "Addressing Suboptimal Anticoagulation in Atrial Fibrillation: Uncoupling the Potential for Factor XI/XIa Inhibition for Stroke Prevention."

I'm absolutely delighted to be joined today by my good friends and colleagues.

First, Jeff Weitz, who's professor of medicine and biochemistry at McMaster University in Hamilton, Ontario. And Christian Ruff, who's with me at Brigham and Women's, he's the director of general cardiology and a senior investigator with me at the TIMI Study Group and an associate professor of medicine at HMS.

Gentlemen, welcome.

Christian T. Ruff, MD, MPH : Thank you.

Jeffrey I. Weitz, MD, FRCP(C), FACP, FCCP: Thank you.

Dr Sabatine: Let me set the stage. Atrial fibrillation is of course very common. Probably affects about 10 million individuals in the United States. The prevalence is about 10% to the elderly. Lifetime risk, maybe 25% or so. Thought to be the cause of about 1 in 7 strokes.

Many of us trained in an era where warfarin was the only oral anticoagulant. And then the direct oral anticoagulants, the factor IIa, the factor Xa, inhibitors came along roughly in the mid-2000s in terms of the large trials. Christian, you helped lead one of those trials at the TIMI Study Group and did the definitive meta-analysis.

What did we learn about the direct oral anticoagulant (DOAC) class?

Dr Ruff: Yeah, it was an exciting time now. Over a decade ago, as you mentioned, over a half a century, we only had warfarin and other vitamin K antagonists. And while effective, they were associated with significant rates of bleeding, particularly intracranial hemorrhage, which we know is very severe and potentially life threatening.

And the NOACs as a class were really remarkable drugs. They were certainly as effective, if not more effective, in reducing ischemic stroke, which is important. There's a number of reasons why those drugs were developed, but they were markedly safer with respect to serious bleeding, predominantly intracranial hemorrhage, reducing that risk by over 50%, which was really a major advance.

And it was that reduction in serious bleeding that actually drove the observed 10% mortality benefit of the DOACS vs warfarin. With respect to less severe types of bleeding -- say major bleeding, bleeding that leads to hospitalization -- their benefit was less clear. They tended to reduce bleeding in general, but they were associated with a 25% increase in gastrointestinal (GI) bleeding, which we know is about two thirds or three quarters of the bleeds we see in an atrial fibrillation population.

And that has really hampered a bit of their use worldwide today.

Dr Sabatine: Great. And then, Jeff, getting us back to mechanism, that increased signal for GI bleeding, just help the listeners understand why that might be the case?

Dr Weitz: I don't think we know exactly, but we postulate that it's due to the fact that these are active agents in the gut, so you have active drug in the gut, so if you have a lesion there, an ulcer, or a tumor, they exacerbate the bleeding from that lesion.

And even though dabigatran is a prodrug, it is activated by esterases in the gut. So it actually gets activated there. And that's different from warfarin, which has to go through the liver and reduce the synthesis of all the clotting factors. And so any effect it has on the gut is indirect through systemic anticoagulation.

Dr Sabatine: So then the DOACs -- and really, of them, probably the Xa inhibitors are kind of the dominant ones now -- started for atrial fibrillation, recommended over warfarin for the work, Christian, that you and many others did that then really were a major advance in the field. But Jeff, are patients with atrial fibrillation being appropriately treated with anticoagulation, and if it's not optimal, what are the barriers?

Dr Weitz: Well, I think that even the most contemporary registries tell us that at least 30% of eligible patients with atrial fibrillation are not getting anticoagulants, even not getting treatment with the direct oral anticoagulants. And those that... are getting the direct oral anticoagulants, there's still a large overuse, and inappropriate use of the low-dose regimens with the belief that by lowering the dose, they'll be safer.

And yet, what we find is that they're not safer and they reduce the stroke prevention activity.

I think we still have an unmet need for safer anticoagulants that will increase uptake of anticoagulant therapy to prevent stroke in patients with atrial fibrillation.

Dr Sabatine: And, Christian, your thoughts about the appropriate or inappropriate use of anticoagulation ...

Dr Ruff: Yeah, and I echo what Jeff said. I mean, we were very excited. This was a remarkable advance, because we thought it was this serious, life-threatening bleeding was really the major impediment to anticoagulation for stroke prevention.

But we realized that bleeding is important to clinicians and patients, and very frequently we have patients who have a bleed, it may not be a life-threatening bleed, but have a bleed and they discontinue therapy, not just around the bleed, but forever, and they're scared to go back on an anticoagulant.

And then we see other patients who haven't bled before, but are deemed to be high risk of bleeding. They're older, they're a little frail. Patient's son or daughter reports they may have fell before, they're on a bunch of other medications, and it's this fear of bleeding that also leads to physicians not to prescribe the anticoagulant at all, even the safer Xa inhibitors, or for the patient to refuse to take it.

Because they're concerned themselves about having a bleed. And so those 2 factors, both patients who have bled before and are really scared to go back on, or this fear of bleeding that I'm at high risk and I don't want to take the chance that I may bleed, has really limited utilization among prescribers and healthcare providers, as well as patients and their families.

Dr Sabatine: Yeah, we're all trained sort of do no harm. I remember as a house officer, people would say, wait a minute, but they seem unsteady. They could fall, right? And people have sort of debunked that, but it's still common in everyone's mind.

Of course, the beauty of medicine is that there's always a drive for innovation, and that brings us to the new kids on the block, right, the factor XI/XIa inhibitors, and so there's no one better in the world, Jeff, than you to help us understand this new class.

Dr Weitz: Yeah, What we've learned over the last few years is that factor XI is critical for thrombosis, but mostly dispensable for hemostasis. In order for a clot to grow and to the point where it occludes a blood vessel, you need back-activation of factor XI by thrombin to amplify clotting. But in terms of hemostasis, when you...

cut a blood vessel because of the hemostatic envelope, with all that tissue factor, you get explosive thrombogeneration. So you don't need that back-activation of factor XI by thrombin.

And that's what makes it uncouple hemostasis and thrombosis, and it attacks thrombosis with little or no effect on hemostasis.

That's why it has the potential to be safer.

Dr Sabatine: That was a beautiful explanation. Oftentimes, the coagulation cascade can induce a little post-traumatic stress disorder (PTSD) for those of us who don't live in the hematology world the way you do, but your explanation was really awesome.

Maybe also just to help set the stage in terms of data we have from genetics, in terms of individuals who are unlucky enough to be born with factor XI deficiency, how do they do clinically?

Dr Weitz: I think we have a number of levels of evidence, so individuals who have congenital factor XI deficiency are protected from thrombosis, and they rarely have spontaneous bleeding. They can bleed with surgery or trauma, but they don't have serious bleeding like we see with other bleeding disorders. And we know from genetic epidemiology studies that persons with low factor XI are at reduced risk for ischemic stroke, for venous thrombosis, probably also for myocardial infarction (MI), and those with high factor XI levels are at increased risk for those thrombotic episodes.

And finally, in animal studies, if you knock out factor XI or if you inhibit factor XI, you attenuate both arterial and venous thrombosis. But you don't get bleeding, which is different than what we saw with the direct oral anticoagulants. If you had an inhibitor of factor Xa or factor IIa thrombin, as you mentioned, with those agents, yes, as you increase the dose, you got more antithrombotic activity, but you also got more bleeding. But that's not what's seen with the factor XI inhibitors.

Dr Sabatine: Well that's, you know, very, very powerful data. I think certainly, as clinical trialists, the genetic validation of the target is quite compelling.

So that's the theory, and that's great. Now there have been trials looking at this new class primarily for venous thromboembolism (VTE) prophylaxis.

Of the different compounds, are there differences in mechanism, in terms of how they work, half-life, et cetera, that people should keep in mind as they're evaluating the data.

Dr Weitz: We have really... 3 types of agents. We've got the antisense oligonucleotide, which reduces the hepatic synthesis of factor XI. We've got antibodies that either inhibit activated factor XI or bind to factor XI and prevent its activation.

And we've got small molecules which bind reversibly to the active site of factor XIa, much like the oral factor Xa inhibitors bind to the active site of Xa, and those oral agents have rapid onset of action after oral administration. Levels peak in about 3 hours. They have half-lives that enable once- or twice-daily administration.

And they have less renal excretion than the Xa inhibitors, but still have some. Then we have the parenteral agents and the antisense oligonucleotides ... takes about 2 weeks before it lowers the levels of factor XI to where you need them to go. And it has a long half-life. And the antibodies, if you give the first dose intravenously (IV), you get immediate action.

If you give it subcutaneously, it takes about a week to 2 weeks before you get a steady state. But you can give it once a month. And again, a long half-life. We have oral agents, very much like our current DOACs. And then we have parenteral agents that have short or fast onset of action, but a long duration of activity.

For the parenteral agents, it really depends on the safety. If it's safe, then parenteral administration might be nice. No renal excretion, no drug-drug interactions, enhanced adherence, which is a problem for elderly patients. But the oral agents could be safer than what we have now, and they'll be very similar to the DOACs, so there'll be familiarity with physicians in terms of how to use them.

Dr Sabatine: It reminds me a little bit, you know, other spaces like the lipid space, there's sort of different approaches, people have different preferences for what they like and for compliance.

And before we get into your take for those trials, just, inhibition of either the synthesis of or locking in factor XI vs inhibiting factor XIa... Any thoughts for that, that viewers should know?

Dr Weitz: Yeah. Inhibiting the synthesis of factor XI or locking it in the zymogen confirmation, the inactive precursor confirmation, prevents you from generating factor XIa at all.

Whereas the XIa inhibitors, you have to wait for XIa to get generated, and then you've got to attack factor XIa before it activates its substrates, does its business. Potentially, reducing factor XIa generation completely could be more effective than inhibiting factor XIa, but it might depend on the indication.

Dr Sabatine: So, so Jeff, you've been heavily involved in most, if not all, of them... what's the takeaway from these trials for VTE prophylaxis with the factor XI inhibitors?

Dr Weitz: When we are evaluating new anticoagulants, we usually start in the orthopedic population because those patients are at high risk for deep vein thrombosis and you can detect it with an x-ray of the veins on venogram.

So it's a good way, in a relatively small number of patients, of efficiently determining the dose response. And what we saw with parenteral agents, like osocimab and abelacimab, and with the oral agent, milvexian, we saw overall, compared with enoxaparin, a 40% reduction in the risk of postoperative venous thromboembolism and a 60% reduction in clinically relevant bleeding, which is the composite of major and clinically relevant non-major bleeding -- so better efficacy without the cost of more bleeding. In fact, we had reduced bleeding.

Dr Sabatine: Yeah, so that's, that's really sort of amazing. And maybe just to put that in context, what about for the Xa inhibitors? How did they fare when they were doing their VTE trials?

Dr Weitz: In the VTE trials, as you increase the dose, you've got better efficacy, but there was more bleeding. And even in some of the phase 3 programs, there was more bleeding than with enoxaparin....

So, we're seeing a better benefit-risk profile with the factor XI inhibitors, but the proof is in the pudding...we need to go to phase 3.

Dr Sabatine: Yeah, so those are very compelling data, as you point out -- early stage, but very compelling -- to try to separate out, as you nicely noted at the beginning, thrombosis from hemostasis. A lot of different ways to try to get at it, but here the science looks very, very solid for that.

Now I'd like to return back to atrial fibrillation (AF). So, Christian, up until now, what have we seen for the factor XI inhibitors in AF? And then also, people are starting to explore some other indications that we've thought about adding anticoagulation but have been... our hand may have been stayed because of the risk of bleeding, so post-MI, post-acute stroke. Tell us about that.

Dr Ruff: Right, and I think atrial fibrillation is the place to start because that's where the most enthusiasm is, you know, it's a huge common condition and it's a class 1 indication for full-dose anticoagulation.

And there was a single study to date, a phase 2 study, and that was the PACIFIC AF study. And it was a study of one of the small molecules, asundexian vs apixaban, which is a very commonly used factor Xa inhibitor. And again, a modest size of trial was only 12 weeks. But in that period of time, 2 doses of asundexian when pooled together basically showed a significant reduction in bleeding compared to apixaban.

All the bleeds were clinically relevant, non-major bleeds, not a lot of bleeds that led to hospitalization. But at least the suggestion that the ... safety that Jeff mentioned, even in a short period of time, seemed evident. That full-dose anticoagulation with a factor XI inhibitor seemed to be potentially safer than our standard of care, factor Xa inhibitors.

Obviously, small trial, limited number of endpoints, but at least sort of that first hint of the promise of factor XI inhibition being a potentially safer anticoagulant.

But obviously, based on that genetic epidemiology, there was also this thought, could we be using it for secondary prevention for non-cardioembolic stroke patients who don't have atrial fibrillation, who have a stroke, as well as secondary prevention of MI? Now, we've used anticoagulants for that in the past, but the cornerstone of treatment in those 2 conditions is antiplatelet therapy. And while adding anticoagulants in the past has been effective, [we've] paid a heavy penalty for bleeding, particularly intracranial hemorrhage, when combining with either single or dual antiplatelet therapy. But given the safety of the factor XI inhibitors, could you add a factor XI inhibitor on top of antiplatelet therapy? And there have been a couple of trials in that space.

There was one trial after acute myocardial infarction, that was the PACIFIC AMI. And that trial, again, small phase 2 trial, but demonstrated that a small molecule of asundexian on top of dual antiplatelet therapy (DAPT) had no statistically significant increased risk in bleeding, which I think was impressive because we hadn't seen that before with the Xa inhibitors, but obviously too small to make any sort of comparisons with regard to efficacy.

For secondary non-cardioembolic stroke, there were 2 trials, AXIOMATIC SSP and PACIFIC STROKE. And again, standard of care after an acute non-cardioembolic stroke is antiplatelet therapy, frequently dual antiplatelet therapy. And adding both of the small molecules, asundexian and milvexian, did not increase the risk of bleeding significantly compared to placebo -- and importantly, in that population, did not increase the risk of intracranial hemorrhage, which has always been the fear of adding an anticoagulant on top of antiplatelet therapy after acute stroke.

And so I think both trials, really all the trials, reassuring with the safety aspect. Across 3 different conditions, atrial fibrillation, non-cardioembolic stroke, and recurrent MI. That it seems the addition of an anticoagulant, either alone or in combination with antiplatelet therapy, seems to be relatively safe, but obviously need definitive phase 3 trials with regards to the efficacy.

Dr Sabatine: That's a fantastic summary.  I think the takeaways are in a relatively short trial looking at atrial fibrillation without a lot of major bleeding events, it looked okay for a factor XI inhibitor, so that's good, that's with an active comparator. Then you mentioned in other conditions where we have been burned by bleeding, even with the Xa inhibitors, that it looked relatively good. I mean, I guess as you look at the data, maybe some trends for increased in bleeding, but it's against placebo in those cases. And as you pointed out, not really for sort of serious bleeding. So that's reassuring, and I think that helps keep the door open.

As you pointed out, none of those trials are powered to look at ischemic events. You need much bigger trials for that. Jeff, turning back to you, your take on the trials that Christian commented on.

Dr Weitz: Well, the PACIFIC AF trial was vs an active comparator, apixaban, and apixaban is considered by many to be a very safe DOAC. So, the safety advantage was impressive. Short follow up, underpowered for efficacy, but safety looks good.

The 2 stroke studies, the one with asundexian, the one with milvexian, there's some... commonality between them, although they missed their primary efficacy outcome, which was recurrent symptomatic stroke and covert stroke detected by repeat brain imaging. Both of them showed that if you looked at symptomatic stroke, there was a reduction, particularly in those patients with atherothrombotic type of stroke.

So I think that together, the data are consistent. The MI study underpowered, and although you mentioned that we have the

ATLAS trial with rivaroxaban early after an acute coronary syndrome, and we have the COMPASS trial late after showing that dual pathway inhibition is better than single modality treatment,

so the potential is in the ACS patients you could start a safe agent on top of maybe dual antiplatelet therapy, go to single antiplatelet therapy, keep it going for a long time and get the benefits early, and for long benefits, and do it safely.

Dr Sabatine:  There's good data from COMPASS for the benefit for that. You know, the uptake, I think, has been modest because people still fear bleeding, and so there's been a sort of move to kind of de-escalate therapy because of that risk of bleeding, which... you know, at least in some of the studies, even almost paradoxically, you take away some blood thinner and there's actually a decreased risk of ischemic complications. Maybe some of that is due to the fact that people can stay on their regimen, who knows? But, this then again opens the door for allowing that other pathway, the anticoagulant pathway, to be attacked.

Okay, so early days, numbers still small, but again, again promising.

So, that brings us to abelacimaband AZALEA TIMI 71. These data are quite literally hot off the presses, having just been presented by Christian as a late breaker at AHA 2023, so Christian, we are grateful that you can share the key points with us today.

Dr Ruff: Yeah, thrilled to be able to share this exciting new data. And AZALEA TIMI 71 is really the largest and longest of the phase 2 trials studying a factor XI inhibitor against comparators in this case for rivaroxaban, one of the Xa inhibitors, and a relatively large trial. We randomized 1287 patients who are at high risk for ischemic stroke and atrial fibrillation to one of 3 arms, either 150 mg of abelacimab, 90 mg of abelacimab, or standard rivaroxaban 20 mg once daily, dose adjusted in select patients. And it is important to note the trial was blinded with respect to the 2 abelacimab doses but open label with respect to abelacimab vs rivaroxaban.

And it was an event-driven trial. We plan to target 166 major or clinically relevant non-major bleeds. And we anticipated that there would be a reduction in bleeding, which is why we did the trial.

But I think we were all surprised earlier this year in September, where our independent data monitoring committee (DMC) recommended termination of the AZALEA TIMI 71 trial for overwhelming reduction in our primary endpoint of major or clinically relevant, non-major bleeds compared to rivaroxaban with a benefit-risk favoring abelacimab. And so the trial's actually actively closing out. And at the AHA we were lucky to present, the data from the last DMC snapshot. And we learned a couple of important things, which you mentioned.

First, that abelacimab provided potent inhibition of factor XI. And we saw greater than 95% inhibition with both the 90 mg and 150 mg dose. And speaking to the mechanism that you mentioned, really prevented the formation of activated factor XI.

And when we looked at the primary endpoint, which we know was going to be impressive, we were really surprised to see that compared to rivaroxaban, substantial significant reductions in major clinically relevant non-major bleeding -- a 67% with the 150 mg dose, a 77% with the 90 mg dose, and commensurate decreases with major bleeding in general, and actually almost eliminated gastrointestinal bleeding, which had been the bleeding I mentioned that's plagued the factor Xa inhibitors.

And so, I think really exciting results, the largest and the longest trials, I think really confirmed the promise of factor XI that it may be markedly safer compared to, or even our standard-of-care anticoagulants, the DOACs, and really I think sets the stage then to turn our attention to efficacy, which is really going to be defined by the phase 3 trials.

Dr Sabatine: Well, it's super spectacular, you did a fabulous job presenting it, and, The data really speak for themselves, and it validates, Jeff, what you had talked about in terms of the genetics for that. So it is gratifying when the clinical trial data actually validate the epidemiology, the genetics for it.

As you noted, bleeding has been the Achilles heel for the prescription of oral anticoagulants. It stays people's hands appropriately or inappropriately, as you pointed out, in many cases. And it may be, it may be that now with this new class, we may have solved that problem.

So, Jeff, you were obviously of great help when we were designing and executing the study. Your take on the results?

Dr Weitz: Oh, I think it's phenomenal data because it speaks to the safety of factor XI inhibition, potent factor XI inhibition, as we would expect from its mechanism of action, an extended period of factor XI inhibition, and an elderly population, I think the median age was something like 75 years?

Dr Ruff: Yeah. 74, exactly. It was an older patient population, so if you can inhibitor factor XI safely over a long period of time, it speaks to the safety of this mechanism of action, and a potent inhibitor.

Dr Sabatine: That's right, and as you pointed out, Christian, you know, having the benefit of the prolonged inhibition, right? That's what you really need to see, because that's going to more closely approximate what's going to happen to our patients when we start giving these drugs.

Dr Ruff: Who are on it lifelong...

Dr Sabatine: Right.

Dr Ruff: ...anticoagulation for atrial fibrillation in particular.

Dr Sabatine: No, for sure. So, the results really were very striking. It still is a phase 2 trial. Clearly we need larger phase 3 trials that are going to give us the definitive answer. Christian, help us sort of start to wrap up by commenting on what are the phase 3 trials for the factor XI inhibitors that are coming down the road, some of which have now already started and are well along the way.

Dr Ruff: Right, exactly. Generating a lot of enthusiasm for these phase 3 trials, which will hopefully lead to their approval in various different spaces. And they really touch on all the areas we mentioned. There's efforts in venous thromboembolism. There are 2 trials being done with the antibody abelacimab in cancer-associated VTE, which you know, high-risk patients for recurrent VTE, a lot of bleeding risk.

And those 2 trials, MAGNOLIA or ASTER, are in general cancer-associated VT and one focusing on GI malignancies, which have a lot of GI bleeding, which have plagued the factor Xa inhibitors. Then there are efforts in secondary stroke, stroke, non-cardioembolic stroke, and we have 2 large trials being done there with asundexian and milvexian, the LIBREXIA-Stroke, and then the OCEANIC STROKE trials, and so really trying to define the ability of factor XI inhibition on top of, really, DAPT in the early period after stroke to see if that's a safe and effective strategy. And there's a single trial in acute coronary syndrome, LIBREXIA ACS, and that's really looking then at administration of milvexian on top of antiplatelet therapy to prevent recurrent MI.

And probably still the largest group of trials remain atrial fibrillation, where really anticoagulation has that outsized role. And actually four phase 3 trials in atrial fibrillation, they're really split into 2 camps. There are 2 trials studying long term the efficacy, really defining the ability to reduce ischemic stroke and systemic embolism compared to apixaban.

And there are 2 trials, LIBREXIA-AF, with milvexian, and then OCEANIC-AF, with osindexian. Those are large trials against, that's the standard of care, apixaban.

And then there were 2 other trials that are really looking at a vulnerable population. High-risk patients with AF who are also very high risk of bleeding and are deemed ineligible even for our safest current anticoagulants, can't even be prescribed a DOAC. And those 2 trials are the LILAC-TIMI 76 trial with abelacimab and the OCEANIC-AFINA trial with asundexian. And that's actually against placebo in patients who aren't getting anything -- which we know, as you mentioned, a substantial group of patients -- to see if maybe an incredibly safe anticoagulant has a role in those most vulnerable patients who currently aren't receiving anything.

And so I think really sort of a broad spectrum of phase 3 trials in multiple disease areas on the arterial side, on the venous side, all of these agents. So I think these next few years are going to be really exciting while we wait for those landmark trials to conclude.

Dr Weitz: And I think as you mentioned earlier, we have trials that are going head to head with apixaban in atrial fibrillation. We have trials in venous thromboembolism that are going head to head with abelacimab vs apixaban in the people who are at lower risk for bleeding or dalteparin a low-molecular heparin in the higher risk.

And then we have the placebo-controlled trials, even in AF and then with the acute coronary syndrome (ACS), and the secondary stroke prevention. So we really are looking at factor XI inhibition in several different ways.

Dr Ruff: Every possible combination.

Dr Sabatine: Oh, it's going to be, right, probably approaching about 100,000 patients, between all of this, put together. So, it's really an amazing program.

We're nearly out of time. Maybe, sort of, using your crystal balls, thinking about with the new data coming, we're assuming it plays out as we think. Where do you think the uptake for the factor XI inhibitors will be first or of the highest priority as people start thinking about changing practice?

Obviously, we need to see what the trials show, but if it goes as planned, where do you think? Jeff, you want to start off?

Dr Weitz: Well, if we take the AZALEA results and look at safety there in patients with atrial fibrillation, if the efficacy is there, why wouldn't we be treating our atrial fibrillation patients with a factor XI inhibitor?

And then we have areas where we haven't dared to go before, like ACS or secondary stroke prevention, where we're going on top of antiplatelet therapy if an anticoagulant, dual pathway inhibition is better than antiplatelet therapy alone. Again, that would be a phenomenal indication.

Dr Sabatine: Yeah, and huge populations. Christian?

Dr Ruff: Yeah, I agree. I mean, I think we know that assuming the efficacy is reaffirmed, which is always the most important thing, we know that with respect to antithrombotic therapy, whether it's antiplatelet or anticoagulant, safety drives physician preference. So, if these agents are as safe as we think they are, there's going to be tremendous enthusiasm for patients and physicians. I think broadly, people are going to want to use them.

I think one of the things we will struggle with as a healthcare society is, should we be using them in everybody because they are so effective and so much safer. Or will, you know, as these agents, the fact that Xa inhibitors become generic, will we say, you know there are some patients who do quite well on them and maybe we should reserve these [factor XI inhibitors] to these high-risk patients.

Those are some of the struggles we're going to have in various health systems. But to be able to be on an incredibly safe anticoagulant that doesn't require frequent stopping and starting around procedures. You take atrial fibrillation, 25%, 30% of those patients a year after the diagnosis have a procedure within one year.

So the ability to be on these agents, not worry about trauma, other antiplatelet agents, procedures, I think, would be a remarkable advance that would really streamline care for patients and I think make people a lot more comfortable on potentially being on a long-term, even lifelong, anticoagulant, which still, I think, evokes a lot of fear in both patients and providers.

Dr Sabatine: I think, you know, need to give first a thank you to our hematology professors in med school, who tried to make sure we learn the entire coagulation cascade and it turns out all the factors are actually important.

Dr Ruff: I should have paid attention.

Dr Sabatine: Yeah. Yeah. This may be factor XI's moment now to be in the sun.

So Jeff, Christian, thank you so much for your insights. And thank you to the audience for participating in this activity. please do continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited

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