In this episode I’ll:
1. Discuss an article about the factor Xa reversal agent andexanet alfa.
2. Answer the drug information question “What is the treatment for cryptococcal meningitis in a non-HIV infected, non-transplant patient?”
3. Share a resource for lectures and handouts by a board certified toxicologist.
Show notes at pharmacyjoe.com/episode121.
Before we begin, I’d like to share a pearl from my book, A Pharmacist’s Guide to Inpatient Medical Emergencies:
“Causes of low Hgb: blood loss, coagulopathy, hemolysis (may be from meds!), DIC” #pharmacists https://t.co/w0tP1mmQW7
— Pharmacy Joe (@PharmacyJoe) September 12, 2016
Article
Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors
Lead author: Stuart J. Connolly
Published in New England Journal of Medicine online August 2016
Background
Factor Xa inhibitors still lack a reversal agent. Fresh frozen plasma or prothrombin complex concentrates represent a “hemostatic attempt” but do not directly counter the effects of rivaroxaban and apixaban. Ciraparantag, a broad-spectrum reversal agent discussed in episode 75 is not commercially available. It appears that andexanet alfa, a recombinant modified human factor Xa decoy protein, is getting closer to meeting the standard for FDA approval.
Andexanet alfa has already been shown to reverse the inhibition of factor Xa in healthy volunteers.
Methods
This study was multi-center, prospective, open-label, and single-group. The investigators evaluated 67 patients who had acute major bleeding within 18 hours after the administration of rivaroxaban or apixaban. The study protocol was for each patient to receive a bolus of andexanet followed by a 2-hour infusion. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. Patients were followed for 30 days after receiving andexanet.
Results
The site of bleeding was predominantly gastrointestinal or intracranial. The mean time from emergency department presentation to the administration of the andexanet bolus was 4.8 hours. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis. Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.
Conclusion
The authors concluded:
On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%.
Discussion
While a reversal agent for oral factor Xa inhibitors is needed ASAP, the number of thrombotic events in the study is concerning. Numerically this number is much higher than with FFP or PCC. The 12 events that occurred were:
1 myocardial infarction
5 strokes
7 deep-vein thrombosis
1 pulmonary embolism
Some patients had more than 1 event.
70% of the population was taking an oral factor Xa inhibitor for atrial fibrillation, but only 35% of the thrombotic events were related to atrial fibrillation (5 strokes).
I’m a lot less excited about andexanet after reading this article due to the high number of thrombotic events. Hopefully, a study comparing andexanet to usual care will be conducted. As of the time of this recording, no such study is registered at clinicaltrials.gov.
Drug information question
Q: What is the treatment for cryptococcal meningitis in a non-HIV infected, non-transplant patient?
A: Amphotericin B deoxycholate plus flucytosine for four weeks, then fluconazole 400 mg daily for eight weeks, then fluconazole 200 mg daily for 6 to 12 months.
To answer this question, I consulted the 2010 Infectious Disease Society of America guidelines for the management of cryptococcal disease.
Resource
Bryan Hayes, also known as @PharmERToxGuy on Twitter has started an emergency medicine / toxicology blog at pharmertoxguy.com. Bryan’s debut blog post is about whether prothrombin complex concentrates should be given to patients before lumbar puncture. While you are there, check out Bryan’s lecture recordings and handouts which he has made freely available.
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If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
Enjoyed the articles and focused “quick” review of reversal agents.
Thank you!
I was wondering, the dose of fluconazole you quoted for cryptococcal meningitis treatment was 400mg then 200mg. Is there any consideration for using a weight based dosing? and if so, which would take priority (Standardized dosing vs. weight based)?
Thanks for great episode.
Do you know of any data evaluating adverse thrombotic events associated with PCC use for reversing xarelto and apixiban since you listed that the 18% associated with a andexant is higher than those reported with FFP and PCC. Only thrombotic adverse events data with PCC that I can find is the ones associated with reversing Coumadin.