Cite this post as:
Guest Author. EMCrit – I Have Issues with Andexanet by K. Kipp, PharmD. EMCrit Blog. Published on June 19, 2018. Accessed on January 21st 2022. Available at [https://emcrit.org/emcrit/issues-andexanet/ ].
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Unless otherwise noted at the top of the post, the speaker(s) and related parties have no relevant financial disclosures.
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Xa activity needs to be stopped just long enough for coagulation to allow for clot formation only. That is enough to get hemostasis except in the larger bleeds that were still not controlled (about 10%). This has not yet been studied for urgent surgery indication, which will likely need an entirely different dosing scheme. Price might come down when they have large scale Gen 2 manufacturing approved next year. They only have 40 hospital supply so it’s not surprisingly that it’s expensive. Meanwhile, COGS is 25% and they spent half a billion to get the drug to market. I don’t… Read more »
I think she made it clear. How long are we going to continue andexxa infusion? The whole day? Does it really worth it? She probably missed the point that the severity may dectate the duration of infusion. But this should be obvious. Additionally, risk of thrombosis should be taken into consideration as in Annexa-4 thromboembolic events occured in 18%.
Thank you for addition on to my post – I didn’t miss the point that severity of the hemorrhagic event will likely determine the duration of the infusion. If you are still bleeding — I will still give you the drug. Yes- agree thrombosis risk of 18% should be noted, but not significant. Based on the study- andexanet does not increase the risk of thrombosis if you dig further. If you assess each patient case who threw a clot post-andexanet- 18% is not surprising. The final thrombosis risk for the study is ~11% (its an ongoing trial- 18% is based… Read more »
“FDA and the company have been thinking about this for years, not the past week.”
Yes, the drug companies definitely put patient interests above profits. They’d never bring something to market too early just to make some more money
Interesting view on the FDA. If you follow Nasdaq/Dow or stock market drama- but andexadet and Portola Pharmaceuticals is featured pretty frequently. I can assure you the CEO received a bunch of heat from his shareholders when andexanet was initially denied by the fda. What other reason would you bring a drug to the market? to start generating revenue…
I might be misreading your view of the FDA’s role with regards to “bringing a drug to the market.” Regards – KKipp
Response from 06/25/18- my comments are bolded Xa activity needs to be stopped just long enough for coagulation to allow for clot formation only. That is enough to get hemostasis except in the larger bleeds that were still not controlled (about 10%). This has not yet been studied for urgent surgery indication, which will likely need an entirely different dosing scheme. Price might come down when they have large scale Gen 2 manufacturing approved next year. They only have 40 hospital supply so it’s not surprisingly that it’s expensive. Meanwhile, COGS is 25% and they spent half a billion to… Read more »
While the price is disappointing, you do realize there is more data available: interim data on safety outcomes for 227 patients and adjudicated efficacy outcomes for 132 patients. 61% had ICH- higher than all other reversal agent trials. At 30 days, 12 percent of patients had died and 11 percent had a thrombotic event. They also evaluated achievement of clinical hemostasis within 12 hours of administration. A simple google by the author would have been nice prior to writing this.
Initial response 06/20- Yes, all of the above are correct. I did include the outcomes in the article. They did achieve hemostasis 12 hours after the end of the 2 hour infusion. Since it took ~4 hours to start the andexanet – patients were really assessed at 18 hours after presentation to the ED. It’s an ongoing trial and I presented data during the time frame of Annexa-4. Investigators carefully selected their endpoints and trial design and overall. I think they did a decent job. I was suck on the pricing – so I wanted to point out various components… Read more »
I don’t think it takes 4 hours to start the drug, more like 15 minutes for our pharmacy. Where did you hear 4 hours?
Hi Mark, Correct in real life it does not take ~4 hours. I spoke with a couple of the investigators of the trial and it took approximately 30-45 minutes to reconsistute the vials. Penn just added it to our formulary and I have not used it yet. If the dose requires 18- 100 mg vials- it will take at least 30 minutes to mix. Once Portola Pharmacueticals Gen 2 plant gets up and runny- Andexxa will be manufactured in a different vial size. Mean (± SD) time from ED presentation to the administration bolus was 4.8 ± 1.8 hours. Thank you… Read more »
Thanks for the fast response. I think most patients get low dose, so 15mins not 30mins for most. Gen2 is 200mg vials, reduces the # of vials in half, so could be even shorter prep time? Also, I need to double check but I don’t think expired goods are stuck.
Hello!
Could you elaborate on your reasoning behind not getting anti-xa levels in the ED to help guide the decision to reverse with andexanet? We are discussing utility of this at my institution. UFH or LMWH calibrated anti-xa levels (depending on your reagent sensitivity) may be able to qualitatively determine if a patient has factor xa inhibitor still floating around. If a patient is negative, we save money and prevent administration of a drug that promotes thrombin generation in patients with a baseline hypercoaguable state.
Curious about your thoughts!
Response from 06/20/18: Great question! My comment regarding obtaining Xa levels – I feel this adds on to the complexity of managing patients in the critical setting. For patients with any intracranial hemorrhage/trauma or unstable GI bleeds- these patients should receive the Xa reversal agent regardless of the baseline Xa level. However, when it comes to GI bleeds that are stable- I currently do not jump to give these patients Kcentra. So I am unsure the value of the Xa level in this scenario. I agree Xa levels could help guide therapy in specific patients. When it comes to life… Read more »
I started out very excited about this drug (circa 2104) but now feel the same as the author. Portola clearly has a lot to learn. They botched the initial approval and manufacturing roll out (should have had this in 2016). They decided to spread the high dose over 18 vials (18!!) and they priced a single dose above the average american’s annual salary (let that sink in…. 1 years wages for the average american). Facepalm.
No conflicts of interests, other than working for a hospital.
Agree. Its a rookie company which a great drug that I would love to use. I have been looking forward to this drug becoming available. I think they did a great job with the study design. But when I read the approximate cost – I just shook my head. Its like they picked a number from a hat. Thank you for the post. -KK
It is expensive medicine for sure. FDA asked Portola to conduct a phase 4 trial, which is expensive too. The cost adds up. Someone has to pay for it. I think it is the US drug regulation to be blamed for the drug price
Gotta admit that it’s pretty annoying that the dose is spread out in 9 or 18 vials. And also they sell the drug in boxes of 4 vials. Neither 9 or 18 is divisible by 4.
Thank you for the information. I am not surprised. how long does it take to reconstitute?
4 factor PCC is “standard of care”? Based on what data? Giving PCC has 0 impact on preventing any of the DOACs ability to inhibit the active enzyme Xa. It’s simple enzymology :E + I = EI. PCC has no impact on this chemical equation. I agree that andexanet doesn’t “clear” the drug, but it will reduce levels and allow Xa to work. But PCC administration in this setting is equival;ent to placebo.
Based on the consensus from human clinical trial data. Correct, Kcentra has no impact on Xa inhibitors. 4FPCC is administered to overcompensate or outweigh the Xa inhibition. Its effective in the setting of major hemorrhagic events – based on published data and feedback from neurosurgeons and trauma docs and any other physician doing procedures in the emergent setting. 4FPCC bridges the patient until the drug wears off. There is a clear distinction between 4FPCC and placebo.
Thank you for your feedback-
This doesn’t make sense to me. PCC adds certain clotting factors. Thrombin restoration/ generation (and thus one’s ability to clot and stop a major bleed) remains impaired, as it is still dependent on Xa working. Xa is necessary at the end of the clotting cascade, irrespective of how many other factors you overload via PCC upstream. PCC doesn’t clear out Xa inhibitors nor does it add Xa. Adding PCC creates a prothrombotic state once the body naturally clears out Xa inhibitors, no?
Correct. Since factor Xa is being inhibited from completing the coagulation cascade, 4FPCC theoretically provide the clotting factors to augment the anticoagulant effect. If I have a patient with a life-threatening bleed, my goal is stop the bleeding and/or prevent expansion of the bleed. Based on the mechanism and kinetics of 4FPCC, I can assist the patient’s ability to clot as the patient metabolizes and eliminates the Xa-inhibitors (rivaroxaban, apixaban).
Thank you for your feedback —
Just stumbled onto this; I wrote similar blogs at the time. I enjoyed the back and forth. IMHO, this is you most “leaky” argument. Just how much PCC is needed to “overwhelm” the Xa inhibition? Answer is now one knows for sure, and folks who have tried to come up with this really are only using things like PT/INR reversal to estimate it, which are also not clearly linked with outcomes.
Just my two cents.
Good news! CMS approved the NTAP for andexanet alfa which will reimburse hospitals 50% of the wholesale acquisition cost of the standard dose which is expected to be $14,062.50 which will be paid in addition to the DRG reimbursement to the hospital. This will be in effect at the start of the 2019 Fiscal Year on October 1, 2018 which will be before most hospitals acquire their first dose of andexanet alfa as Gen 2 product won’t be approved for sale until after that date. For the sickest patients with acute major bleeding due to rivaroxaban or apixaban, this will… Read more »
Thank you for this information. This certainly eases the decision to use this drug in the inpatient setting. Its more comparable to the current treatment regimens from a pricing perspective.
Appreciate your follow-up!
I grow a little tired of hearing about KCentra in this patient population and how Andexxa has no outcomes data. If CSL Behring would do an actual trial in reversal of anti-Xa inhibitors they could share the market with Andexxa. Instead, they raked in money year after year with off-label use. If they were confident in their chance of success, they would have ran this trial rather than lose this market to Andexxa. Our ER docs want to use the FDA indicated product PERIOD. Also, CMS is providing $15k per admission to help cover the cost of Andexxa so they… Read more »
I’d like to post a follow on comment due to the recently ~1.5 weeks ago epublished ahead of print CHEST guidelines for 2018. It looks like the debate of KCentra vs Andexxa is settled. CHEST recommends Andexxa and other specific reversal agents be used first ie Praxbind for dabigatran reversal vs non-specific agents ie KCentra. It goes on to say that non-specific agents are “less effective in reversing coagulation abnormalities, have not been shown to improve outcomes, and are prothrombotic”. In light of these recommendations, who echo ASH, AHA, and ESC recommendations to first use specific reversal agents that hospitals… Read more »
Thanks Brent for this update and information. Happy to see CHEST published their recommendation for managing Xa bleeds. Based on the feedback of clinicians who have used andexanet, I have been told that it certainly works. I have been looking forward to using this drug in clinical practice. From a legality perspective, I am unsure if a physician could be liable if the fda approved drug is not on hospital formulary. If P&T approves the drug- we are going to use andexanet for the Xa bleeds over Kcentra. I am sure many for profit hospitals will not put andexanet on… Read more »
There is no evidence to support the conclusion that Andexanet is superior to 4F-PCCs as the two have not been compared in head to head in RCTs (although a clinical trial is currently underway (https://clinicaltrials.gov/ct2/show/NCT03661528?term=NCT03661528&rank=1). Rates of thromboembolic events are comparable (4F-PCC 3-8% vs. Andexa 10%). The annexa-4 trial was a non-randomized, open-label, single arm trial that excluded ICH patients with GCS <7, planned surgery within 12 hours, and those with expected survival <30 days. Despite excluding the sickest patients, mortality was still 14%. Based on this trial, it is not appropriate or clinically responsible to state that andexa is… Read more »
So what the major guideline organizations sold out to big pharma years ago. We are smart enough to analyze one study ourselves.
Kristina — I agree with you, I have serious issues with Andexxa too! Maybe I’ll be pleasantly surprised and it turns out to be a wonder drug but for now…skeptical. I’m hoping a large medical center/trauma center publishes, presents a poster at major conference, or shares their medication use evaluation comparing internal Andexxa vs. Kcentra outcomes for Xa reversal next year. Perhaps 6 months Kcentra then x6 months Andexxa then compare cost, thrombosis, clinical homeostasis, morbidity, mortality, etc… Bottom line- I want to see a head to head and likely a large trauma center will do their own MUE. No… Read more »
I haven’t checked beck on this subject in a while, but it still amazes me that even with CHEST & UptoDate’s strong language recommending against Kcentra and for Andexxa that people still continue to debate this. Kcentra is offlabel! Andexxa carries an FDA indication for reversal of DOACs. If someone here can honestly say if they have a major brain bleed in themselves or a family member that they’d rather roll the dice with an offlabel, prothrombotic product that has no evidence of improving outcomes over Andexxa I would be VERY, VERY surprised. Like me and the ER docs are… Read more »
How about no data that it has any clinical benefit, reduction in hemorrhage, and also carries “prothrombotic” risks?
As someone who reverses ICH on a daily basis, I have really not noticed any difference between it and Kcentra.
I loved this post. I think it reviews the pros and cons nicely and sums up initial thoughts about the drug that a lot of us have. I was not aware of the logistics issue with the number of vials needed so thank you for including that. To those commenting that we shouldn’t be looking at price, it would be nice if we could avoid looking at the cost of this medication and focus on giving whatever seems most appropriate, but that is not the reality. Let’s say a hospital adds this drug to formulary. In order to keep enough… Read more »
Really enjoying the discussion on this. I’m obviously a bit late to the game. One thing nobody is talking about is the potential risk of auto-immune disease. This drug is a foreign protein that is designed to mimic Xa. Although probably rare, I wonder if there is any real risk of developing anti-Xa antibodies, which is a scary thought.
As long as we are getting CMS money it is financially viable. But what about when the new technology money stops?
I agree that I’d like to see a head-to-head trial. I think a placebo-controlled trial is unrealistic.
Thank you for your feedback. Great question regarding the antibodies. This comes up frequently- and unfortunately we don’t have answers.
no anti Xa-antibodies detected in the full report just published in NEJM. https://www.nejm.org/toc/nejm/medical-journal?query=main_nav_lg
There is no evidence to support the conclusion that Andexanet is superior to 4F-PCCs as the two have not been compared in head to head in RCTs (although a clinical trial is currently underway (https://clinicaltrials.gov/ct2/show/NCT03661528?term=NCT03661528&rank=1). Rates of thromboembolic events are comparable (4F-PCC 3-8% vs. Andexa 10%). The annexa-4 trial was a non-randomized, open-label, single arm trial that excluded ICH patients with GCS <7, planned surgery within 12 hours, and those with expected survival <30 days. Despite excluding the sickest patients, mortality was still 14%. Based on this trial, it is not appropriate or clinically responsible to state that andexa is… Read more »
The other issue is the study concludes that anti-factor Xa levels aren’t significantly correlated with hemostasis. The study in essence found that their endpoint anti-factor Xa levels was not linked to hemostasis. They specifically comment on how anti factor Xa levels can’t be used as s lab value to determine if someone should get andexanet Alfa.