Blog

Andexanet Alpha Approval, Where to Begin?

Posted by gulseth.michael on May 10, 2018 at 10:00 AM

One thing I love about my job is it never gets boring…….


Unless you live under a rock, I am sure you are aware the first specific reversal agent for factor Xa inhibitors has been approved. The full package insert can be found at: https://www.andexxa.com/prescribing-information/


Now, as an antithrombotic pharmacist, I’ve been following the development of this agent very closely for years. Here is a list of issues I am immensely interested in:


1. Pricing. In my field, they are in a league of their own. I was thinking, based on other market agents, they’d price around $10,000 for low dose and $20,000 for high dose, but I was not even close. The exact price is about $27,500 per gram, so even low dose infusions (most apixaban for example) will be close to $25,000. (Note infusion length; see below.)


2. Data with the agent is remarkable that since it was a technological breakthrough, it has never been compared to no agent/placebo, or clotting factor agents like prothrombin complex concentrate (PCC). Further, while not high quality data, there is some data suggesting PCC is useful in life threatening Xa inhibitor bleeds.1 With that said and in fairness to andexanet, I get nervous raising physiologic levels of clotting factors to supra-physiologic levels which is what PCC does in these patients.


3. There is a potential concern that andexanet inhibits tissue pathway factor inhibitor potentially inducing a hypercoagulable state.2, 3 The agent has a boxed warning since thrombotic events were noted in the trial, but since there was not a comparator, it is impossible to know if this was normal disease course in patients inherently at risk of thromboembolism or an issue with the reversal agent.


4. The agent has a very short ½ life, much shorter than the agents it will be used to reverse. Is an infusion of a bit more than 2 hours (when bolus included) really enough time for every single patient? Note they have not done a surgical reversal trial. Also, the price is based on a 2 hour infusion after the bolus.


5. Is this the formal dawn where all facilities need rivaroxaban and apixaban calibrated anti-Xa levels? You can make a strong argument it could make sense to check the levels after stopping the infusion in some cases and using them to help guide care. (Not to mention they are better at directing initial care, too, than pt/INR too.)


6. Availability. Most will not be able to access this medication until at least 2019.


So, what do anticoagulation clinicians need to do in light of all of this?


1. Engage your pharmacy and hospital administration now. They need to understand and appreciate the potential financial ramifications of this agent. You have time to do this before it is available.


2. Engage critical medical staff groups, such as hospitalists, emergency department physicians, cardiologists, intensivists, pharmacists, neurologists, trauma surgeons, and neuro surgeons now, not after the drug is released. They need to know what we know, what we don’t know, and the price of therapy.


3. Update your reversal orders before this drug is released, and release them when it is. The dosing is complicated based on agent and timing, and errors are very likely. Further, take steps to assure clinicians follow the recent ACC/AHA consensus decision pathway on bleeding management. http://www.onlinejacc.org/content/early/2017/11/10/j.jacc.2017.09.1085?_ga=2.196811172.901783200.1525897874-344143112.1519406263


4. Do what is possible to educate and put in guidelines this should not be used immediately in most GI bleeds. They key point being the antidote could be worse than the poison in those situations.


5. For pharmacists, get yourself to the bedside as much as possible in these situations. You have a key role to play in helping guide individual care due to your knowledge of pharmacology and pharmacokinetics. I can think of no better way to show value to your organization, and document your activities.


Questions for discussion that I hope some of you will comment on:


1. Considering the data issues, price, and possible thrombotic risk, will any hospitals decide not to put this on formulary and simply use PCC?


2. What are you going to do specifically to limit use to only the patients who really need it?


3. How are you going to deal with the financial ramifications of potential length of the infusion creep?


4. Are any of you going to pursue setting up research based rivaroxaban and apixaban levels at your facility? We have them and are using them already in this population as an initial lab.


References


1. Schulman S, Gross PL, Ritchie B, et. al. Prothrombin complex concentrate for major bleeding on factor Xa Inhibitors: a prospective cohort study. Thromb Haemost. 2018 Mar 21. doi: 10.1055/s-0038-1636541. [Epub ahead of print]


2. Lu G, Lin J, Curnutte JT, Conley PB. Andexanet Alfa, a Universal Antidote Under Development for Factor Xa Inhibitors, Reverses Rivaroxaban-Induced Inhibition of Thrombin Generation Initiated By the Intrinsic Coagulation Pathway Independent of TFPI [poster]. American Society of Hematology 58th Annual Meeting. December 3-6, 2016; San Diego, CA. Abstract 3831.


3. Lu G, Lin J, Coffey G, Curnutte JT, Conley PB. Interaction of andexanet alfa, a universal antidote to fXA inhibitors, with tissue factor pathway inhibitor enhances reversal of fXA inhibitor-induced anticoagulation. Journal of thrombosis and haemostasis : JTH. 2015;13:634-635.


Michael P. Gulseth, Pharm. D., BCPS, FASHP

Categories: None

Post a Comment

Oops!

Oops, you forgot something.

Oops!

The words you entered did not match the given text. Please try again.

Already a member? Sign In

0 Comments