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Optimal reversal strategies for factor Xa (FXa) inhibitor-associated intracranial hemorrhage (ICH) have garnered much attention in recent years. The use of four-factor prothrombin complex concentrates (4PCC) as a viable option in the management of FXa inhibitor-associated ICH has been seemingly confirmed with recent data.¹ However, optimal dosing of 4PCC for this indication remains under debate. Fixed-dose regimens as well as weight-based regimens of 25 or 50 units per kilogram (units/kg) have been described. The purpose of this article is to compare the 25 vs. 50 units/kg dosing strategies of 4PCC for FXa inhibitor-associated ICH.  

Team 50 Units Per Kilogram

Hematoma expansion (HE) leading to neurological deterioration is one of the greatest fears in the management of FXa inhibitor-associated ICH. Mortality rates are lower than those of warfarin-associated ICH but may still be as high as 27%, and it remains unclear whether HE can be utilized as a surrogate predictor of poor outcomes.^2,3 Given this uncertainty, it is not unreasonable for clinicians to target maximum reversal of any medication-induced coagulopathy to mitigate HE.

In the largest study of 4PCC for FXa inhibitor-induced ICH to date, Panos et al. retrospectively evaluated a multicenter cohort of 663 patients, with 433 being eligible for assessment of efficacy.⁴ Among eligible patients, 81.8% had excellent or good hemostasis with a median initial dose of 44 units/kg.Twenty-nine patients received a second dose of 4PCC due to either HE or sustained coagulopathy noted in repeat laboratory data, with 22 of these patients receiving an initial dose of <35 units/kg. These findings suggest that a higher dose of 4PCC may be more effective, but concern for generating unnecessary thrombotic risk persists, as 3.8% of patients in this study suffered subsequent thrombotic events. Reassuringly, however, the rate of thromboembolic events did not significantly differ when doses of >30 units/kg vs. ≤30 units/kg were compared in a recent meta-analysis of 4PCC use in FXa-associated major bleeding.⁵ Lastly, Davis et al. conducted a multicenter, retrospective study which examined the use of a high- (≥35 units/kg) vs. low-dose 4PCC regimen (<35 units/kg) in 89 patients with FXa inhibitor-associated ICH (74 in the high-dose and 15 in the low-dose groups).⁶ There was a significantly higher percentage of patients who achieved hemostasis within the high-dose group (89.2% vs. 46.7%, p=0.002), but no statistically significant differences in mortality, length of stay, or thrombotic events.

Current Neurocritical Care Society guidelines suggest that oral FXa inhibitors be reversed with 4PCC or activated PCC at a dose of 50 units/kg (a conditional recommendation based on low-quality evidence).⁷ This recommendation is also echoed by the American College of Cardiology and American College of Emergency Physicians’ guidance on reversal of FXa inhibitor-related bleeding.^8,9 Often, the last known ingestion time of the FXa inhibitor is unobtainable. Since specific anti-Xa calibrated assays are not routinely available or utilized to assess drug presence, clinicians must assume elevated serum drug concentrations until proven otherwise, which makes it reasonable to consider administering the high-dose strategy. However, there is currently limited evidence studying the relationship between FXa inhibitor serum concentration and effectiveness of reversal in this population. 

Team 25 Units Per Kilogram

Anticoagulation reversal requires a delicate balance between achieving hemostatic efficacy and minimizing the risk of subsequent thrombosis. Current guideline recommendations for high-dose 4PCC for FXa inhibitor-associated ICH reversal are based on data originating from healthy volunteers and animal models of hemorrhagic injury.^7,10,11 These studies do not accurately reflect the complexity of critically ill ICH patients with regards to efficacy or safety of high-dose therapy, and do not consider the risk of thrombosis in those with underlying prothrombotic conditions. In recognizing the limitations of the data guiding these recommendations, investigations have been ongoing to define the optimal 4PCC dosing strategy that employs the lowest dose necessary to achieve hemostasis while mitigating risk of thrombosis. Several studies have been published describing similar efficacy of weight-based 4PCC dosing of 25 or 30 units/kg, with hemostatic efficacy rates of 83.8% and 94.7%, respectively.^12,13 However, these studies are limited by their small sample sizes and lack of comparator arms.^12,13

Several recent publications have sought to directly compare low-dose to higher-dose 4PCC for FXa inhibitor-related major bleeding. Wilsey et al. retrospectively compared patients who received low- (20 – 34 unit/kg) or high-dose 4PCC (35 – 55 unit/kg) for FXa inhibitor-associated major bleeding, with ICH accounting for 65.9% of major bleeds. No significant difference in hemostatic efficacy (75.4% vs 78.6%, p=0.715), thrombotic events (5.4% vs. 2.4%, p=0.635), or hospital length of stay (11.3 vs. 12.5 days, p=0.07) was identified between the low- and high-dose groups, including the ICH subpopulation.¹⁴ In a retrospective, multicenter cohort study evaluating 93 patients with FXa inhibitor-associated spontaneous or traumatic ICH, there was no difference in hemostatic efficacy between low- (25 units/kg) or high-dose (50 units/kg) 4PCC at 82.3% and 83.9% respectively, and no difference in thrombotic events, need for blood products or surgery, or hospital length of stay.¹⁵ Similar outcomes were demonstrated in a retrospective analysis of 47 patients with FXa inhibitor-associated major bleeding comparing 25 units/kg and 50 units/kg of 4PCC, with similar hemostatic efficacy (87.5% vs. 91.3%) but a lower risk of thrombosis and inpatient mortality in the low-dose group.¹⁶

It is also important to highlight additional benefits of low-dose 4PCC including cost-saving implications and the potential to expedite time to reversal agent administration. With an average wholesale price (AWP) for Kcentra® of $2.90 per unit, the mean cost of reversal for a 70-kg patient  would be $5075 for a 25 units/kg dose compared to $10,150 for 50 units/kg dose. Kcentra® is available in 500- or 1000-unit vials and is dosed based on factor IX component which ranges from 400–620 units to 800–1240 units per vial size, respectively. Therefore, using the same example as above, for a 70-kg patient using the 500-unit vial a 25 unit/kg dose would require 3 – 4 vials for reconstitution compared to 6 – 9 vials for 50 units/kg. The time needed to compound these products can be a lengthy process and any reduction in the need for reconstitution can aid in facilitating faster time to administration of the drug product. 

Conclusion

The optimal dose of 4PCC for FXa inhibitor-associated ICH remains unknown. However, there are compelling data for both the 50 and 25 units/kg regimens as described. A continued focus on FXa inhibitor-associated ICH should aim to determine factors that could contribute to HE and poor outcomes beyond just optimal 4PCC dose (e.g., time to administration, concomitant antithrombotic use, or degree of organ dysfunction). Additionally, we need to ensure we are capturing patient-centric measures of efficacy beyond radiological outcomes. Randomized controlled trials comparing the various dosing strategies and how they relate to functional outcomes are still needed. We know high-quality robust data sets are necessary to answer this question; however, in the interim please let us know on Twitter which dosing strategy you currently implement at your institution by tweeting this article and using the hashtags (#Team50NCS or #Team25NCS). 

References

• Nederpelt CJ, Naar L, Krijnen P, et al. Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding: A Systematic Review and Meta-Analysis. Crit Care Med. 2021 Oct 1;49(10):e1025-e1036.
• Xian Y, Zhang S, Inohara T, et al. Clinical Characteristics and Outcomes Associated With Oral Anticoagulant Use Among Patients Hospitalized With Intracerebral Hemorrhage. JAMA Netw Open. 2021 Feb 1;4(2):e2037438.
• Huttner HB, Gerner ST, Kuramatsu JB, et al. Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor-Related Atraumatic Intracerebral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care. Stroke. 2021 Oct 14: STROKEAHA121034572.
• Panos NG, Cook AM, John S, et al. Factor Xa Inhibitor-Related Intracranial Hemorrhage: Results From a Multicenter, Observational Cohort Receiving Prothrombin Complex Concentrates. Circulation. 2020 May 26;141(21):1681-1689.
• Milioglou I, Farmakis I, Neudeker M, et al. Prothrombin complex concentrate in major bleeding associated with DOACs; an updated systematic review and meta-analysis. J Thromb Thrombolysis. 2021 May 23. doi: 10.1007/s11239-021-02480-w.
• Davis SD, Chauv S, Hickman AW, et al. High-dose versus low-dose 4-factor prothrombin complex concentrate for factor Xa inhibitor reversal in intracranial hemorrhage. Thromb Res. 2021 Dec;208:112-116. doi: 10.1016/j.thromres.2021.10.026. Epub 2021 Oct 30. PMID: 34749042.
• Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016 Feb;24(1):6-46.
• Baugh CW, Levine M, Cornutt D, et al. Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel. Ann Emerg Med. 2020 Oct;76(4):470-485. 
• Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020 Aug 4;76(5):594-622. 
• Herzog E, Kaspereit F, Krege W, et al. Four-factor prothrombin complex concentrate reverses apixaban-associated bleeding in a rabbit model of acute hemorrhage. J Thromb Haemost. 2015; 13(12):2220-2226.
• Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131(1):82-90.
• Berger K, Santibañez M, Lin L, Lesch CA. A low-dose 4f-pcc protocol for doac-associated intracranial hemorrhage. J Intensive Care Med. 2020;35(11):1203-1208.
• Allison TA, Lin PJ, Gass JA, et al. Evaluation of the use of low-dose 4-factor prothrombin complex concentrate in the reversal of direct oral anticoagulants in bleeding patients. J Intensive Care Med. 2020;35(9):903-908.
• Wilsey HA, Bailey AM, Schadler A, Davis GA, Nestor M, Pandya K. Comparison of low- versus high-dose four-factor prothrombin complex concentrate (4f-pcc) for factor xa inhibitor–associated bleeding: a retrospective study. J Intensive Care Med. 2021;36(5):597-603.
• Cascone AE, Daley MJ, Pan N, Padilla‐Tolentino E, Milling TJ. Low‐dose versus standard‐dose four‐factor prothrombin complex concentrate for factor‐Xa inhibitor reversal in spontaneous and traumatic intracranial hemorrhage. Pharmacotherapy. 2021;41(6):501-507.
• Hormese M, Littler A, Doane B, et al. Comparison of high- and low-dose 4-factor prothrombin complex concentrate for the emergent reversal of oral Factor Xa inhibitors. J Thromb Thrombolysis. 2021;52(3):828-835.