Washington University Emergency Medicine Journal Club – October 2024
Dr. Brian Cohn
Hello all,
This month at journal club we will be looking at options for the reversal of anticoagulation with apixaban and rivaroxaban in life-threatening hemorhage. Specifically, we will look at articles comparing PCC to andexanet.
The PGY-1 paper will be assessed using the Meta-Analysis form, the PGY-2 and PGY-3 papers will be assessed using the Therapy form, and the PGY-4 paper will be assessed using the Economic Evaluation form.
Vignette
You are working in TCC one weekend when you get a page that a 72-year-old female
is en route by EMS after an MVC with head strike and positive LOC. GCS is reportedly
13 and vital signs are stable. On arrival, the pt is confused, opens eyes to voice, and
follows commands. Her vitals are stable. She has a hematoma to her right forehead,
moves all extremities, has symmetric breath sounds, and abdomen is soft,
nontender, and nondistended.
The patient is taken to CT scan where she is found to have a large right frontal
subdural hematoma with a large component of subarachnoid hemorrhage in the
right frontal and parietal lobes. There is significant mass effect and 5 mm of midline
shift.
Upon review of her records you find that she is on Apixaban for paroxysmal atrial
fibrillation. After giving IV mannitol and IV keppra, you consult neurosurgery who
requests that you reverse the patient’s anticoagulation given the presence of a lifethreatening
bleeding. You are uncertain whether you should administer Kcentra
(Prothrombin Complex Concentrate) or whether the high cost of andexanet alfa is
warranted. Initially the pharmacist recommends PCC, but the neurosurgeon later
says they specifically want to administer andexanet. After ordering the medication,
you wonder whether the evidence truly supports andexanet over PCC for lifethreatening
intracranial hemorrhage, and what the evidence shows for other lifethreatening
bleeding. After the patient is taken to the Neuro ICU for further care, you
decide to search the literature…
PICO Question
Population: Adult patients with life-threatening or uncontrolled bleeding in the
setting of factor Xa inhibitor use (apixaban or rivaroxaban)
Intervention: Andexanet alfa
Comparison: Prothrombin complex concentrate
Outcome: Mortality, bleeding control, functional status, cost
Search Strategy
PubMed was seated using the terms andexanet AND “prothrombin complex
concentrate”, which resulted in 131 unique citations (https://tinyurl.com/
praph9re). Among these, 2 retrospective comparison studies, one systematic review,
and one economic comparison were chosen for inclusion.
Article 1: Ferreira LO, Oldemburg RAL, Leitã o Filho JM, et al. Andexanet Alfa versus
Four-Factor Prothrombin Complex Concentrate for the Reversal of Factor Xa (FXa)
Inhibitor-Associated Intracranial Hemorrhage: A Systematic Review of Retrospective
Studies. J Clin Med. 2024 May 24;13(11):3077. [Answer Key].
Article 2: Pham H, Medford WG, Horst S, et al. Andexanet alfa versus four-factor
prothrombin complex concentrate for the reversal of apixaban- or rivaroxabanassociated
intracranial hemorrhages. Am J Emerg Med. 2022 May;55:38-44. [Answer Key].
Article 3: Dobesh PP, Fermann GJ, Christoph MJ, et al. Lower mortality with
andexanet alfa vs 4-factor prothrombin complex concentrate for factor Xa inhibitorrelated
major bleeding in a U.S. hospital-based observational study. Res Pract
Thromb Haemost. 2023 Aug 30;7(6):102192. [Answer Key].
Article 4: Micieli A, Demchuk AM, Wijeysundera HC. Economic Evaluation of
Andexanet Versus Prothrombin Complex Concentrate for Reversal of Factor Xa-
Associated Intracranial Hemorrhage. Stroke. 2021 Apr;52(4):1390-1397. [Answer Key].
Bottom Line
Since the advent of direct oral anticoagulants (DOACs) as an alternative to warfarin for the treatment and prevention of thromboembolic events in the late 20th century, management of bleeding with these agents has been an ongoing endeavor (Salter 2022). While the risk of major bleeding with DOACs is reduced compared to vitamin K antagonists, it remains around 2 to 4% per year (Siegal 2019). Initially, nonspecific reversal agents such as prothrombin complex concentrate (PCC) were used to reverse the anticoagulant effects of DOACs with promising effect in most patients (Majeed 2017). Andexanet alfa, a recombinant modified factor Xa protein, was approved by the FDA in 2018 for reversal of the anticoagulant effects of factor Xa inhibitors (apixaban and rivaroxaban in the US) in the setting of life-threatening or uncontrolled bleeding. To date, there have been no head-to-head studies comparing the effectiveness of PCC and andexanet alfa in the reversal of anticoagulation by factor Xa inhibitors.
While there have been no prospective studies comparing outcomes between these two treatment strategies, several retrospective studies have been reported. Two such studies—one a chart review of 109 patients from a multi-center healthcare system in central Florida (Pham 2022), the other a large cohort study of nearly 5000 patents from 354 US institutions in 42 states (Dobesh 2023)—offer conflicting results. The smaller study included only patients with ICH, and found no significant difference in rates of the primary outcome of excellent hemostasis on neuroimaging (RR 1.0, 95% CI 0.77 to 1.31), median percentage change in hemorrhage volume, incidence of thrombotic events (RR 0.88, 95% CI 0.26 to 2.94), or inpatient mortality (RR 1.62, 95% CI 0.87 to 3.04). The median total cost of treatment with andexanet was significantly higher ($23,602) compared to PCC ($6692). Conversely, the larger study, which included all hospitalized patients with rivaroxaban- or apixaban-related bleeds who received andexanet or PCC, found a 50% reduction in the odds of death during hospitalization for those treated with andexanet compared with PCC (OR 0.50, 95% CI 0.39 to 0.65); a similar reduction in in-hospital mortality was seen among those with ICH (OR 0.55, 95% CI 0.39 to 0.76) and GI bleeds (OR 0.49, 95% CI 0.29 to 0.81). Several factors could account for these differences, including risk of selection bias in both studies (compounded by nonavailability of andexanet in 6.5% and PCC in 18.4% of centers in the second study), vastly different sample sizes, and differences in the included hospitals themselves.
A systematic review of studies on this topic, published earlier this year, found similarly conflicting results (Ferreira 2024). Among 11 retrospective and observational studies—not all of which measured all outcomes—3 found no difference in mortality, 1 demonstrated higher mortality among those receiving andexanet, and 2 found higher mortality among those receiving PCC. Similarly, 7 studies found no significant difference in bleeding stabilization or cerebral hemorrhage volume on neuroimaging while 2 found andexanet to be superior. There were an equal number of studies demonstrating higher rates of thrombotic events with andexanet and with PCC (4 each). Of note, with the exception of the study by Dobesh et al (n = 1328), these were all small studies with sample sizes of 109 or less.
Given the lack of clear clinical superiority of one treatment over the other, it is worth considering the associated costs. While both treatments remain quite expensive, there is a significantly higher cost associated with andexanet alfa compared to PCC. In an effort to incorporate cost-effectiveness into decision-making, a retrospective study used a Markov cohort model to compare costs and outcomes in patients with intracranial hemorrhage (ICH) who received IV andexanet alfa in the ANEXXA-4 study and patients who received 4-factor PCC in the UPRATE 2017 study (Micieli 2021). Andexanet had the highest discounted life expectancy of 2.53 years and a discounted quality-adjusted life expectancy of 1.55 QALYs, while PCC had a discounted life expectancy of 2.09 years and a discounted quality-adjusted life expectancy of 1.28 QALYs. The authors conclude that andexanet alfa represents low value for reversal of factor Xa–associated ICH with an incremental cost-effectiveness ratio of $219,652 per QALY gained and as such is not cost-effective. Unfortunately, cost is not universal where medicine concerned, and one should consider the costs both to the healthcare system and to the patient based on one’s practice location when weighing these two potential treatment options.