Episode 1: Factor Xa Inhibitor Reversal Using PCC with Brian Gilbert

Brian Gilbert, PharmD, BCPS, BCCCP
Emergency Medicine Pharmacist

Pharmacology

AgentApixabanRivaroxabanWarfarinDabigatran
Mechanism of ActionFactor Xa Inhibitor Factor Xa Inhibitor Inhibitor of Vitamin K dependent clotting factors (II, IX, VII, and X) Direct
thrombin
inhibitor
Tmax3–42–441.25–3
1/2 Life125-94012-17
EliminationRenal (27%
unchanged drug)
Renal (36% unchanged
drug)
Renal, primarily as
metabolites
Renal (80% unchanged
drug)
Mantha S, et al. Clin Pharmacol Ther 2013;93(1):68 77.

Bleeding Risk

Mantha S, et al. Clin Pharmacol Ther 2013;93(1):68 77.

Prothrombin Complex Concentrate Products and What’s in Them?

  • Profilnine SD and Bebulin
    1. Unactivte PCC, 3-Factor
    2. Cogulation Factors
      1. II, IX, X
  • Kcentra
    • Unactivated PCC, 4-Factor
    • Coagulation Factors
      • II, VII, IX, X
  • FEIBA
    • Activated PCC, 4-Factors
    • Coagulation factors
      • II, VII, IX, X
  • NovoSeven
    • Activated factor VIIa
    • Coagulation Factors
      • Recombinant VIIa

Clinical Literature

Title Berger K, et al. A Low-Dose 4F-PCC Protocol for DOAC-Associated Intracranial Hemorrhage. J Intensive Care Med. 2019 Apr 14. [Epub ahead of print]  
Aim/Clinical ? The objective of this study was to evaluate the effectiveness and safety of a low-dose 4F-PCC protocol in DOAC-associated ICH, through assessment of hemostatic effectiveness and thromboembolic events.
Design This was a retrospective study
Population 19 ICH patients who were 18 years of age or older and received at least one dose of 4F-PCC for DOAC associated ICH
Inclusion/Exclusion Patients who received 4F-PCC at an outside hospital were excluded
Intervention 25 units/kg 4F-PCC per the hospital reversal guideline
Comparison No comparator group
Baseline Characteristic Included 68.2% of patients taking rivaroxaban and 22.7% taking apixaban. 50% were male and the median age was 79.5 yrs. Mean dose of PCC 2000 units
Outcomes – Hemostatic effectiveness was 94.7% overall (18/19 patients). 

– Hemostatic effectiveness was 92.9% for rivaroxaban, 100% for apixaban, and 100% for dabigatran reversals.

(9.1%) developed thromboembolic events after 4F-PCC administration.

– One patient developed an ischemic stroke 0.5 days after 4F-PCC; the second patient developed a left lower extremity DVT 7.3 days after 4F-PCC.

-Hospital mortality was 18.2% (4/22 patients)
Conclusion This study observed a high hemostatic effectiveness rate with a lower dose of 4F-PCC compared to current guideline recommendations. Two patients developed thromboembolic events within 14 days of 4FPCC administration, including one patient who received a repeat dose.
Thoughts 36.8% (7/19 patients) of our evaluable patients had a SAH which carries a lower likelihood for hematoma expansion. Follow-up duration of 14 days to assess for thromboembolic events, While several studies have used a longer assessment period. The hemostatic effectiveness definition was based solely on the documented interpretation of CT head imaging, which was not independently reviewed by a neurosurgeon or neurologist. Many of the patients received platelet transfusions, as this study dates included patients treated prior to publication of the PATCH trial.
Title Dager WE, et al. Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. Thromb Res. 2019 Jan;173:71-76.
Aim/Clinical? To evaluate the outcomes of our dosing approach in patients prescribed a DOAC and experiencing a bleeding event.
Design Single-center, retrospective analysis
Population 64 patients who received FEIBA to treat a bleeding event or mitigate potential bleeding during a high-risk procedure
Inclusion/Exclusion Patients were excluded if they were not receiving a DOAC, had any form of hemophilia, were pregnant, a prisoner, or<18 years of age
Intervention Low dose FEIBA < 20 units/kg  vs Moderate dose FEIBA (24.3 units/kg)
Comparison No placebo group
Baseline Characteristic Mean age 74 yr old, 80% on anticoagulation for Afib, 29% had ICH, 16 % had GI bleeding. 25% on dabigatran, 31% on apixaban, 44% on rivaroxaban
Outcomes Of the 64 patients in the analysis, an additional dose was requested in 6 patients. (90.62% hemostasis)

– 30 day event rates included 5 thromboembolic events (8%) and 9 (14%) patients expired.

Follow-up CT-imaging for ICH, endoscopy/colonoscopy, or interventional radiology exams did not reveal any clinically concerning active bleeding or hematoma expansion except in 2 ICH patients with slight expansion between imaging sessions.

Reduction of apixaban specific Anti-Xa by 76% and rivaroxaban by 56% at 3.3 hours post aPCC
Conclusion 25 units/kg FEIBA or lower appears to be safe and have the potential to expedite hemostasis in critical bleeding settings.
Thoughts This was a single-center, non-randomized retrospective analysis with no comparator. Only a low and moderate FEIBA dosing cohort was evaluated, limiting any comparison to higher doses that have been explored.

Future Studies

https://clinicaltrials.gov/ct2/show/NCT03661528

References:

  • Dabi A, et al. Crit Care Res Pract 2018;4907164.
  • Smith S, et al. J Thromb Thrombolysis. 2019 Apr 2.
  • Berger K, et al. J Intensive Care Med. 2019 Apr 14.
  • Dager WE, et al. Thromb Res. 2019 Jan;173:71-76.
  • Schulman S, et al. Thromb Haemost 2018;118:842 51.
  • Santibanez M, et al. J Crit Care 2018;48:183 90
  • Allison TA, et al. J Intensive Care Med 2018 Epub ahead of print].
  • Tao J, et al. J Intensive Care 2018;6:34.
  • Majeed A, et al. Blood 2017;130:1706 12.

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