Finally, we have the ongoing saga of Andexxa, properly known as “coagulation factor Xa [recombinant], inactivated-zhzo”. The conditional approval for Andexxa in the United States hinged upon single-arm studies and apparent hemostatic efficacy. However, prior to the availability of this specific reversal agent for factor Xa inhibitors, clinicians have been utilizing prothrombin concentrate complexes to treat major bleeding events. The ANNEXA-I trial aimed to compare this PCC-based stopgap “standard of care” against Andexxa for the treatment of intracerebral hemorrhage.⁵

As is the fate of many trials whose procedures, enrollment, and reporting is orchestrated by pharmaceutical companies, the topline results are misleading. Looking narrowly at their primary outcome of hemostatic efficacy, defined primarily by change in intracerebral hematoma volume, the trial favors Andexxa. However, a full 15 percent of those in the “standard of care” cohort were not treated with PCCs and an excess of patients in the Andexxa cohort were lower-risk types of intracerebral bleeding such as subdural hematomas. More troubling, however, were the poor patient-oriented outcomes observed in the trial. Patients in the Andexxa cohort suffered a substantially greater number of thrombotic events, including ischemic stroke and myocardial infarction, and the mortality in patients receiving Andexxa was actually higher at 30 days. A greater number of patients randomized to “standard of care” attained modified Rankin scores of 0 to 3 than the Andexxa cohort, as well. It may be the case Andexxa clearly reduces factor Xa inhibition and attenuates hematoma growth, but the primacy of patient-oriented outcomes clearly ought to caution clinicians about its use.

In summary, continue to expect further permutations for potential treatment in extended time windows. The march towards tenecteplase continues unabated, while reteplase has re-emerged for further investigation. Prehospital blood pressure control in undifferentiated stroke syndromes should not be considered. Finally, the Andexxa marketing push continues, but it’s clear harms cannot be ignored.

Dr. Radecki (@emlitofnote) is an emergency physician and informatician with Christchurch Hospital in Christchurch, New Zealand. He is the Annals of Emergency Medicine podcast co-host and Journal Club editor.

References

1. Li G, Lin Y, Yang J, et al. Intensive ambulance-delivered blood-pressure reduction in hyperacute stroke. N Engl J Med. 2024;390(20):1862-1872.
2. Albers GW, Jumaa M, Purdon B, et al. Tenecteplase for stroke at 4. 5 to 24 hours with perfusion-imaging selection. N Engl J Med. 2024;390(8):701- 711.
3. Xiong Y, Campbell BCV, Schwamm LH, et al. Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombectomy. N Engl J Med. 2024;391(3):203-212.
4. Li S, Gu HQ, Li H, et al. Reteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2024;390(24):2264-2273.
5. Connolly SJ, Sharma M, Cohen AT, et al. Andexanet for factor xa inhibitor–associated acute intracerebral hemorrhage. N Engl J Med. 2024;390(19):1745-1755.