As a cardiology research fellow, Siddharth Patel, MD, MPH, found himself at the headwinds of a relatively rare moment in therapeutic development: a promising new mechanistic class of agents (factor XI inhibitors) for an immensely prevalent condition, atrial fibrillation, in which current treatments pose a clinical conundrum: risk of bleeding.

The backstory to the promising new class illustrates the power of translational science. The clotting factor the therapies target, factor XI, was discovered by observing people who were born deficient in factor XI, then figuring out the biology and reverse-engineering agents to mimic the deficiency. Now the first of these are in phase three clinical trials, one of which Patel is co-leading.

Patel is now an associate physician in the Cardiovascular Division at Mass General Brigham, an instructor of medicine at Harvard Medical School, and an investigator with the Thrombolysis in Myocardial Infarction (TIMI) Study Group. His research on factor XI mechanisms was supported through a 2024 K12 training award from Harvard Catalyst.

Treating atrial fibrillation often means balancing efficacy in stroke prevention with bleeding risk. How does your research address that clinical dilemma?

Atrial fibrillation is estimated to affect one in three individuals over their lifetime, making it one of the most common conditions we encounter in clinical practice. The most feared complications are ischemic stroke or systemic embolism: people with atrial fibrillation have a five-fold higher risk for either. Anticoagulation therapy reduces that risk.

Direct oral anticoagulants, or DOACs, are used and recommended across clinical practice guidelines to treat patients with atrial fibrillation. As with any blood thinner, though, there is an increased risk of bleeding. In many cases, prior bleeding or even the fear of bleeding results in undertreatment. We know from different datasets that 30 to 40 percent of patients with atrial fibrillation remain suboptimally treated and therefore are at higher risk of stroke or systemic embolism. There’s been a real need for safer anticoagulants.

Meanwhile, both observational and genetic studies of people with congenital factor XI deficiency show that these patients, in contrast to people with other types of hemophilia, rarely have spontaneous bleeding and have a lower lifetime risk for ischemic stroke. These data have ushered in the development of a novel class of anticoagulants called factor XI inhibitors.

My K12 project and ongoing research pose several questions: Is there a specific magnitude of inhibition needed to prevent ischemic events without a trade-off in bleeding risk with factor XI inhibition? Which patients with atrial fibrillation are most likely to benefit from one of these new anticoagulants if they come on the market?

What are you learning about the mechanisms of factor XI inhibition and how that relates to bleeding risk?

The thought is that, unlike many of the other clotting factors that are essential for both thrombosis and hemostasis, factor XI only plays a role in propagation or extension of thrombus once it’s been established but may be dispensable for hemostasis. It’s not in the common pathway of the clotting cascade, as are all the other factors that have been targeted by anticoagulants. For example, warfarin targets factors II, VII, IX, and X, and the direct oral anticoagulants target either factor II or X. All of these are in the common pathway.

Because of this mechanistic difference, we may finally have a way to uncouple hemostasis from thrombosis. The thinking used to be that there’s no free lunch – you can’t really prevent clotting without increasing bleeding. Based on what we know from patients with congenital factor XI deficiency, there’s a good hypothesis that targeting factor XI may allow us to finally uncouple these two.

Efforts have been undertaken to target this factor in the clotting cascade, and several therapeutic agents are now in development. These range from oral small molecule inhibitors in the form of a pill that patients take twice a day or daily, to injectable monoclonal antibodies, and even to agents based on siRNAs, which are small interfering RNA molecules that actually suppress the production of factor XI.

How did you get involved in this research?

After the clinical portion of my cardiology fellowship, I pursued a research fellowship with the TIMI study group, an academic research organization that leads cardiovascular outcomes trials. We were involved with one of the phase II clinical trials of abelacimab, an injectable monoclonal antibody that targets factor XI, to help characterize its bleeding profile compared to rivaroxaban, one of the commonly used DOACs. This safety study in patients with atrial fibrillation was the first clinical trial that I was involved with as a fellow.

The K12 has been incredibly important. It’s given me time to be able to leverage some of these data sets and dive deeper into identifying the patient phenotypes who may potentially derive greater benefit from these novel therapies should they be approved.

Remarkably, the study was terminated early because there was a substantial reduction in bleeding with abelacimab – by more than 60 percent – over rivaroxaban. Now I’ve come onto faculty and joined TIMI as an investigator and we are leading the phase III trial of abelacimab. We are examining the efficacy of abelacimab to prevent stroke or systemic embolism in patients with atrial fibrillation who are not suitable for currently approved anticoagulants. Efficacy remains an open question, as the data across the field for factor XI inhibition has been somewhat mixed.

What has been the value of the K12 award to your research trajectory?

The K12 has been incredibly important. It’s given me time to be able to leverage some of these data sets and dive deeper into identifying the patient phenotypes who may potentially derive greater benefit from these novel therapies should they be approved. It has also helped me better understand the mechanistic underpinnings of factor XI inhibition, particularly with respect to potency and how that may relate to ischemic outcomes or bleeding risk. I have learned a great deal not just about atrial fibrillation and anticoagulation, but also about the various modeling approaches for risk stratification.

What drew you to want to be a physician-scientist?

Oh, it’s a great question. You know, in taking care of a patient, I sort of always ask why. Why is it that we do what we do? I spend most of my time in the cardiac ICU, and this problem around the risk-benefit of bleeding in thrombosis is one that comes up often. In that acute context, there’s a much higher risk of both bleeding and ischemic events than with a patient that you might see in clinic.

For example, patients in the cardiac ICU commonly have atrial fibrillation in the context of a recent heart attack for which they are commonly treated with stents to open up the blockage. Such patients most certainly need to be on antiplatelet therapy for the stent, but they also need to be on an anticoagulant for the atrial fibrillation. These medications together synergistically increase the risk of bleeding. On top of that, because they’re in the ICU and are critically ill, they may be undergoing procedures which put them at even higher risk of bleeding.

Questions like these are what drew me toward being a physician-scientist, to be able to really inform my practice with evidence-based science and to even generate some of these data to help guide treatment decisions.

In these patient populations, how do I tailor my approach to what I’m going to give for antithrombotic therapy? What is the right decision based on what we can ascertain about their risk in that moment? Questions like these are what drew me toward being a physician-scientist, to be able to really inform my practice with evidence-based science and to even generate some of these data to help guide treatment decisions.