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Major Trial in Atrial Fibrillation Stopped Prematurely
The investigational anticoagulant drug asundexian held great promise as a safer anticoagulant. Its early failure in a Phase 3 trial teaches many lessons
I received a text message from a colleague last night during dinner that a trial we were part of, called OCEANIC AF, was being terminated early by the data safety monitoring board.
This morning, the makers of asundexian had a press release up on its site.
This is huge news in cardiology. But it is also worthy of a column here because we at Sensible Medicine are interested in how new therapies are tested.
Asundexian is a Factor XI inhibitor. It promised a safer way to anticoagulate patients. I could use the coagulation cascade to explain the theoretical reason why the drug could be the ideal anticoagulant. But regular readers know the weakness of biologic plausibility.
I will also show you some Phase 2 data wherein asundexian clearly led to less bleeding than a standard direct acting oral anticoagulant apixaban. Here is a screenshot from a study called PACIFIC AF.
There were other Phase 2 studies that also hinted at less bleeding.
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Here’s the thing: an espresso would lead to less bleeding than any anticoagulant.
You have to show efficacy. That means reducing events caused by clots—like stroke.
The OCEANIC AF trial enrolled patients with AF who had stroke risk factors. Patients were randomized to asundexian or apixaban. The primary outcome was stroke or systemic embolism. The study started only 11 months ago. Our group was enrolling patients in the trial. It was relatively easy to enroll patients.
To have it stopped this early must have meant there was a serious signal of lack of efficacy.
Lessons and Questions:
This surprise illustrates exactly why we need properly powered Phase 3 trials, which measure hard clinical outcomes. It is one thing to reduce a surrogate endpoint—like inhibition of Factor XI, and it is surely a good thing to have favorable safety.
But, ultimately, a new medical intervention has to improve an important outcome as well as or better than standard care. To show that, you need big randomized controlled trials. Asundexian failed.
A major question raised by the OCEANIC termination is whether the failure against apixaban is a class effect or specific to oral asundexian.
At the AHA meeting, we heard results of a study called AZALEA, a Phase 2 trial comparing an injectable Factor XI inhibitor—abelacimab.
Once again, bleeding rates were favorable but stroke rates were numerically higher (yet there were too few strokes to sort out signal from noise). Abelacimab also performed well in the prevention of venous clots after knee surgery.
The final lesson is one that Vinay Prasad often says: scientific discovery in medicine is hard. Most new things fail. This a perfect example.
It’s why I remain a medical conservative. We want innovation. We laud innovation. But innovation is hard.
Before we accept new therapies, we should have proper trials—such as OCEANIC-AF. New therapies should improve important bias-free endpoints. Things like survival and stroke.
Good on the investigators and the company for testing this new drug in the proper way.