From the Editor
Hey folks– I want to introduce Kristina Kipp, PharmD. She will be joining the EMCrit team as our in-house PharmD. She is a Clinical Pharmacy Specialist in Emergency Medicine/Critical Care at Penn Medicine – Chester County Hospital. Kristina graduated with a PharmD from the Philadelphia College of Pharmacy. She went on to complete 2 years of post graduate training at Thomas Jefferson University Hospital specializing in Cardiology and Critical Care. Kristina currently practices at a community hospital of the University of Pennsylvania Health-System which is located 35 miles outside of Philadelphia, PA. Here is her first post–expect more great stuff in the future–EMCrit
I Have Issues with Andexanet
by Kristina Kipp, PharmD
The Emergency Medicine and Critical Care world has been waiting for the Xa reversal agent since the Factor Xa inhibitors, apixaban and rivaroxaban, came to the market.
Andexanet received both US Orphan Drug and FDA Breakthrough Therapy designations and was approved under the FDA’s Accelerated Approval pathway. In the phase 2 trials, ANNEXA-R and ANNEXA-A, studied andexanet in healthy volunteers. The investigators found andexanet rapidly reversed anti-factor Xa activity, with a median decrease from baseline of 97% for rivaroxaban and 92% for apixaban. [2,3]
ANNEXA-4 evaluated andexanet in the management of hemorrhagic events among patients receiving apixaban or rivaroxaban.
ANNEXA-4: Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors
Below are the main highlights of the trial [4]:
- Ongoing, multicenter, prospective, open-label, single-group study. Not a placebo-controlled trial.
- Included 67 patients from April 2015 to July 2016 who had acute major bleeding
- Primary outcomes:
- Percent change in the anti-Xa activity
- Rate of excellent or good hemostatic efficacy 12 hours after the infusion.
- Primary sites of bleeding: GI 33/67 (49%), intracranial 28/67 (42%), other bleeding sites in 6/67 (9%) which included a nose bleed…
- All patients received a bolus followed by a 2-h infusion of the drug.
- Mean (± SD) time from ED presentation to the administration bolus was 4.8 ± 1.8 hours. (what was everyone doing?).
- Clinical hemostasis was evaluated 12 hours after the andexanet infusion, adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis.
- Anti-Xa activity re-elevated at 2 hours post-infusion. When the infusion is discontinued, andexanet starts to dissociate from the Xa inhibitors resulting in the potential to inhibit FXa.
- Thrombotic events occurred in 12/67 (18%)
- During the 30-day follow-up, 15% of the patients died.
How it Works
Andexanet is a recombinant modified Factor Xa molecule that binds and sequesters the FXa inhibitors, rivaroxaban and apixaban. In addition, Andexanet inhibits the activity of Tissue Factor Pathway Inhibitor (TFPI), increasing tissue factor-initiated thrombin generation.[1]
Andexanet has a rapid onset with a half-life of approximately 1 hour.[4] The package insert states 5-7 hours.[1] Based on the phase 2 trials demonstrating the change in anti-Factor Xa activity in healthy volunteers, in addition to the safety profile observed in ANNEXA-4, Andexanet received FDA approval on May 3, 2018.
But Does it Work?
When administered as a continuous infusion, andexanet will block the anticoagulants ability to inhibit FXa. Andexanet decreases anti-Xa levels within 2-5 minutes.[3,4] But does this positive change of an objective endpoint extrapolate to meaningful patient outcomes?
The reversal of anticoagulation with Andexanet persists for ~1 hour after the infusion is completed.[3,4] At or around this time, the investigators found that the anti-Xa levels started to increase. Since andexanet quickly dissipates from apixaban and rivaroxaban, this results in a rebound increase in anti-Xa activity from the unbound Xa inhibitors. [4]
If the patient has increasing anti-Xa levels post-infusion, will the patient end up bleeding again?
Let’s review at a potential scenario that occurs in clinical practice-
A 78F with AF on rivaroxaban 20 mg daily that she has been prescribed for over a year. She presents to the ED with a significant lower GI bleed that started 2 hours ago. The patient is hypotensive and found to have AKI with a CrCL < 30 mL/min. Based on the kinetics of rivaroxaban 20 mg, we can assume the patient has supratherapeutic levels of the anticoagulant due to her AKI and decreased urine output. With decreased UOP, rivaroxaban can accumulate resulting in delayed clearance of the drug from her system. If I start the andexanet infusion on arrival to the ED for her GI bleed and the last 20 mg dose was 3 hours ago, the patient will still have elevated serum concentrations of rivaroxaban after the 2 hour infusion is complete. The andexanet infusion will halt anticoagulation, but the patient's ability to eliminate the drug is really what's key. So during the infusion, the anticoagulant is unable to block FXa allowing normal coagulation to occur. Once I stop the drug in this patient, the rivaroxaban will likely start to inhibit FXa.
The Xa inhibitors are not “cleared” with this agent. This differs from the mechanism of idarucizumab which binds and eliminates dabigatran.
Approved dosing is cumbersome [6]
Below is the recommended dosing which is based on the specific anticoagulant, dose, and the last time it was taken. Just throw a dart and see where is lands.
Price gouging
The published average wholesale price (AWP) is $3300 per 100 mg vial which is consistent with what Portola Pharmaceuticals previously quoted. [6]
Let’s calculate the price of 1 dose using the AWP of $3300 per 100 mg vial.
1 dose = 900 or 1800 mg → each vial contains 100 mg
= 9 or 18 vials (brilliant, lets spend 30 minutes drawing up 18 vials in a critical patient).
→ AWP $26,400 or $59,400 per DOSE
The actual price is probably ~20 % less, but this value provides a ballpark number. What justifies this price?
In current practice, Kcentra 50 units/kg is the recommended dosing for significant Xa bleeds. The price various depending on the institution and patient population it serves. Kcentra costs approximately $1.41 per unit through my wholesaler. If my patient weighs 100 kg, 1 dose of Kcentra = $7,050.
A single dose of andexanet costs more than Medicare reimbursement for an entire CABG admission with or without MCC at my hospital. How can a drug with no definitive outcomes data cost more than a cardiothoracic surgery? Even if this drug reduces length of stay or prevents invasive procedures, I am still not convinced using this drug will be cost effective when looking at the overall picture.
Lastly, if the patient goes to the OR and continues to bleed during the surgical procedure, the surgeon or anesthesiologist may continue andexanet. So the dollar amount keeps climbing.
Market access strategy limits accessibility
Portola Pharmaceuticals announced they would launch andexanet (AndexXa) under an Early Supply Program in June 2018 with a broader commercial launch in early 2019. The CEO added his take on the process by stating: “due to limited supply in the first six months we will focus on a limited number of hospitals to get AndexXa to patients who need it most.” [5]
Wait- only pre-selected hospitals can access andexanet because their patients need it the most? Based on what?
What Now?
Many institutions have already reviewed andexanet for formulary addition. I am uncertain how hospitals will approach using andexanet in clinical practice if the price is not dramatically reduced. My institution reviews andexanet for formulary addition in July.
Main points to emphasize:
- Does andexanet work? Probably – its mechanism prevents Xa inhibition and allows for normal coagulation to occur. Would I like to see it compared to placebo or Kcentra? Yes, but since it received numerous designations by the FDA, comparative studies were not required to obtain approval. [7]
- Anti-Xa activity re-elevated post infusion. [1] Not surprising, it has a short half-life. If your patient is unstable and still bleeding, do you continue the infusion? Remember- andexanet does not facilitate clearance of Xa inhibitors.
- Portola Pharmaceuticals, a fairly inexperienced biopharmaceutical company, overpriced their drug substantially to the point where hospitals will not be able to purchase it.
- I am not checking anti-Xa levels in the ED to determine whether or not the patient receives andexanet.
- Ultimately, until we have clinical experience using this agent and perform quality, comparative studies, we will not be able to determine if andexanet is more efficacious than the current standard of care (4-factor PCC).
In conclusion, despite the shareholder predictions, Andexanet will never be a “blockbuster drug” because the pricing strategy is not realistic. How do you bring an outrageously expensive drug to the market without the robust outcomes data to justify its price? Every patient case will be billed as an outlier. Portola Pharmaceuticals is providing a disservice to the US healthcare system. The patient who experiences the life-threatening bleed that is unable to access this drug is the one who pays the price the most.
Also See
- Podcast 203 : New Reversals for New Anticoagulants with Nadia Awad
- EM Lit of Note on Annexa 4
- First10EM on Annexa 4
References
- Andexxa (andexanet alfa) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals, Inc; May 2018.
- Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; 375:1131–1141.
- Ghadimi K, Dombrowski KE, Levy JH, Welsby IJ. Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Expert Rev Hematol 2016; 9: 115-22.
- Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373: 2413-24.
- Portola Pharmaceuticals' CEO William Lis on Q3 2017 Results – Earnings Call Transcript. November 06, 2017. https://www.msn.com/en-us/money/companies/portola-pharmaceuticals-ptla-ceo-william-lis-on-q3-2017-results-earnings-call-transcript/ar-AAuwAuC. Assessed on May 31, 2018.
- Lexi-comp: Andexanet alfa Prescribing Information. Last Updated 6/1/18. Assessed June 3, 2018.
- FDA Approval Letter – ANDEXXA. May 3, 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606693.pdf. Assessed on May 31, 2018.
Kristina Kipp
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 of the trial and their approach to market access to demonstrate that their price want not justified by any definitive outcomes data. It’s the most expensive drug that we would use in the inpatient setting.
Great feedback – I should have dived more into the outcomes data. Thank you! -KK
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 Mark for your comment!
KKipp
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 threatening bleeds- I can’t wait for the Xa result to provide treatment that I would have administered anyway. If the anti-Xa level comes back low and the CT head demonstrates ongoing bleeding, I wouldn’t hold off on andexanet. You have an excellent point- and ultimately anti-Xa levels will likely play a role in the treatment algorithm. An algorithm or pathway is needed only because of the significant price. If the patient is on the line- providers are naturally going to consider cost when they make a decision. Overall, when it comes to significant Xa bleeds- I give Kcentra. For insignificant… Read more »
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 actually be a cost saving intervention in addition to decreasing morbidity and mortality. Personally and professionally, I’m looking forward being able to reduce the risk of complications following a major acute bleed in my patients who would benefit from rivaroxaban and apixaban.
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!
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 incentive and too much risk for CSL Berhing or Portola to fund such a study, same way maker of icatibant will never do triple arm head to head comparing icatibant vs. FFP vs. nothing for ACE inhibitor induced angioedema. I work at a busy, major trauma center- one real issue that can lead to wasted money and important to incorporate into decision pathway is for our traumatic patients. I’m thinking the geriatric “fall down go boom” type who comes in alone, paramedic report states patient on Xarelto or Eliquis per witnesses on scene we don’t know their dose or when… Read more »
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 on hand for a single reversal you have to make a $60k investment. But, what if more than one patient comes in one day and needs reversal? We need a second dose. Now the total is $120k. But wait, we have a freestanding emergency department that has to provide the same level of care as the main emergency department. And now we are at $180k. If a hospital keeps this on hand it is going to require a significant investment and there is no safety net for expired or mixed and unused product costs to be recouped. Praxbind offers replacement… 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?
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 obviously see it as a $ saver.
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 and MDs will now almost have to use Andexxa or face lawsuits. The new epublished CHEST guidelines are available from their website and can be seen in their complete for there, but if I recall you can skip to pages 44-48ish for DOAC reversal recommendations.
Brent T
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 formulary. I know of many institutions that do not carry Kcentra.
I feel strongly that Portola over priced this drug to the point that hospitals could lose money on these patient cases (depending on hospital, location, patient population, etc). In addition, they intentionally manufactured their product to an inconvenient vial size (100 mg) to maximize revenue. CEO already left the company- hopefully this indicates something promising.
Thanks for your post Brent! Appreciate the head up on the new CHEST guidelines.
-KK
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 always saying. There’s literally only one argument against Andexxa from any viewpoint. PRICE. If that’s the argument, then consider Soliris sells for almost $600k/year and helps ~1000 patients and brings Alexion $4B/year. Andexxa could sell $1B/yr and save many more lives than Soliris touches. I get it, the price is expensive. But you didn’t see Johnson & Johnson or Bristol Myers out there trying to make an antidote for their $16B/yr in revenue drugs. Tiny little Portola took a chance and did it. As expensive as it has been to get to market and as rare as bleeds are especially… Read more »
$3300X9=$29,700
Pages 34-36 https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM610006.pdf
[…] Review of the drug and its uses by an ED Pharmacist here […]
[…] EMCrit – I Have Issues with Andexanet by K. Kipp, PharmD […]
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 understand your critique of how they’ve are rationing the current supply. That’s all the drug that is available… How else would they do it?
Liability risk will require Andexxa use over 4-PCC, which is not indicated. No hospital will risk a multimillion dollar lawsuit to save $10k. After CMS/Medicaid approves NTAP coverage, there will be no difference in cost between Andexxa and 4-PCC.
Do your homework before writing a scathing article like this… FDA and the company have been thinking about this for years, not the past week.
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 on 67 patients published in NEJM). The safety outcomes data was presented at a national conference last month. The event rate is no different than another other agent used to reverse anticoagulation.
Thank you for your feedback. Just visited arizona- its beautiful! -KK
“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 get the drug to market. I don’t understand your critique of how they’ve are rationing the current supply. That’s all the drug that is available… How else would they do it? I agree- I was disappointed in the price. If they are going to ask for 25-50K for 1 dose, I expect everything else to be flawless. I tried to point out anything that would make someone question how they derived this pricing. Liability risk will require Andexxa use over 4-PCC, which is not indicated. No hospital will risk a multimillion dollar lawsuit to save $10k. After CMS/Medicaid approves NTAP… Read more »
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?