The number of patients requiring chronic anticoagulation has been increasing over the past five years. It was estimated that 7-8 million people were taking these drugs in 2020. Since then, the number of patients taking direct oral anticoagulants (DOACs) has skyrocketed, tripling. At the same time, the use of warfarin has dropped by nearly half.
There was significant concern in the early years of DOACs that they were irreversible agents. If an anticoagulated patient developed a bleed in a critical area (the brain, for example), it could become a fatal problem. Fortunately, the literature has borne out the fact that they appear to be safer than good old warfarin.
A reversal agent for rivaroxaban and apixaban was developed and approved in 2018 based on preliminary studies. A series of studies, named ANNEXA, was performed. The first two were ANNEXA-A and ANNEXA-R. These were Phase 3 trials conducted in healthy volunteers who were pre-treated with apixaban (ANNEXA-A) or rivaroxaban (ANNEXA-R). They showed reversal of “anticoagulation biomarkers” but did not assess clinical hemostasis.
Then came ANNEXA-4, which assessed patients with GI or intracranial bleeding. It monitored the same biomarker (anti-FXa) as before and noted decreased activity, with about 80% of patients achieving “excellent” or “good” hemostasis within 12 hours. However, 30-day mortality was high (15% for intracranial hemorrhage), and the incidence of thrombotic events such as stroke, DVT, PE, or MI was 10% over 30 days.
Finally, ANNEXA-I was a randomized study that examined spontaneous intracranial hemorrhage treated with andexanet alfa or the usual care (usually prothrombin complex concentrate). It found similar reductions in antiFX-a activity, and higher “effective hemostasis.” This is a fudgy number that allowed a comparison between the drug and usual care, yielding a 67% vs 53% efficacy in favor of andexanet alfa. This example was statistically significant but does not appear clinically significant. Offsetting this possible benefit was a higher number of thrombotic strokes and no change in 30-day functional outcome.
Andexanet alfa was approved based on its demonstrated effect on anti-FXa activity, not on efficacy. The company withdrew this drug just a few months ago because the series of ANNEXA studies showed minimal benefit and significant risk.
Bottom line: So what went wrong? We all focused on the mechanism. The drug clearly reduced anti-FXa activity, so it must be working, right? All too often, though, we find that treating the numbers doesn’t always solve the problem and may create more serious ones. Think tight glucose control in the ICU.
When we finally had enough data to see the high complication rates and lack of survival or functional outcome benefit, we could see it was time to pull the plug on this drug. The other major downside was its cost: about $20,000 per dose, and a second dose was nearly always required.
So it’s time to say goodbye to Andexanet alfa. Always remember: in clinical care, outcomes are more important than whether some arbitrary lab number is “fixed.”
Related posts:
- DOAC reversal: Part 1
- DOAC reversal: Part 2
- DOAC reversal: Part 3
- Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage. N Engl J Med. 2024 May 16;390(19):1745-1755. doi: 10.1056/NEJMoa2313040. PMID: 38749032.
