Article

Does a dose relationship exist with prothrombin complex and factor Xa inhibitor reversal? An alternate perspective of Yohe et al.

686 Correspondence / American Journal of Emergency Medicine 38 (2020) 681-689

Table 2

Pediatric weighing practices of Massachusetts emergency departments in 2018, n = 65.

Obtains weight in:

Documents weight in:

n (%)

kg

kg

34 (52%)

both

kg

12 (18%)

both

both

10 (15%)

kg

both

4 (6%)

lbs.

kg

4 (6%)

No policy

No policy

1 (2%)

Abbreviations: kg, kilograms; lbs., pounds; both, kilograms and pounds.

practices. Additionally, there are no data for non-respondents. However, given the high response rate to the survey (89%), we believe our data provides an accurate estimate of current weighing practices in the state of Massachusetts.

In conclusion, despite ten years of pediatric weighing recommenda- tions, a significant portion of Massachusetts EDs still do not obtain and document pediatric weights exclusively in kilograms [7]. Additionally, EDs with a pediatric area were more likely to follow recommended weighing guidelines. A better understanding of barriers to following the guidelines and the possible impact of changing current weighing practices is needed to create interventions that lead to safe and effective patient-centered care.

Funding sources

R Baby Foundation (New York, United States of America).

Author contributions

AAF, EP, KB, CC and JL all contributed to original concept and design of project. AAF and KB contributed to direct survey collection regarding weighing practices from pediatric emergency care coordinators and KB, AFS and CC were responsible for the National Emergency Department Inventory-USA database. AAF, KMB, and JL had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. AAF primarily wrote manuscript with all authors contributing to the editing and review of the manuscript.

Declaration of competing interest

None reported.

Ashley A. Foster MD* Joyce Li MD, MPH

Department of Emergency Medicine, Boston Childrens Hospital, 300 Longwood Ave, Boston, MA 02115, United States of America

E-mail addresses: [email protected] (A.A. Foster)

Table 3 Methods that Massachusetts emergency departments use to measure or estimate weights of children, n = 65.

Obtains weights only in kg, documents only in kg

n = 34

Other weighing practices

n = 31

Weigh with a scale

34

29

Ask parent

21

20

Use Broselow tape

24

17

Estimate weight based on visual

4

7

inspection of child

Other

4

0

Abbreviations: kg, kilograms; lbs., pounds.

Corresponding author at: Division of Emergency Medicine, Boston Children’s Hospital, 300 Longwood Ave BCH3066, Boston, MA 02115,

United States of America.

Emory M. Petrack, MD Department of Emergency Medicine, Floating Hospital for Children Tufts Medical Center, 800 Washington Street, Boston, MA 02111,

United States of America E-mail addresses: [email protected] (E.M. Petrack)

Krislyn M. Boggs, MPH Ashley F. Sullivan, MS MPH Carlos A. Camargo, Jr. MD DrPH

Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114,

United States of America E-mail addresses: KBoggs@partners. org (K.M. Boggs), [email protected] (A.F. Sullivan), [email protected] (C.A.

Camargo), [email protected]. edu (J. Li)

Received 3 June 2019

https://doi.org/10.1016/j.ajem.2019.158424

References

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  8. Gausche-Hill M, Ely M, Schmuhl P, et al. A national assessment of pediatric readiness of emergency departments. JAMA Pediatr 2015;169(6):527-34.
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    Does a dose relationship exist with prothrombin complex and factor Xa inhibitor reversal? An alternate perspective

    We read with great enthusiasm the study by Yohe et al. entitled, “Four-factor prothrombin complex concentrate dose response relation- ships with INR for warfarin reversal.” We applaud the authors for exam- ining Four-factor prothrombin complex concentrate (4PCC) dosing strategies in a unique way given that dose finding studies were never completed for Kcentra(R) [1]. The authors observed that escalating doses of 4PCC were associated with increased in-hospital mortality, and that for every 500-unit incremental increase in dose above 1000 units, a reduction in INR by only 0.02 was appreciated. This is significant given that guideline-recommended and FDA approved dosing strate- gies utilize body weight and initial INR that require higher doses.

    Correspondence / American Journal of Emergency Medicine 38 (2020) 681-689 687

    Multiple retrospective and observational studies have evaluated fixed- dose 4PCC protocols with success in INR reversal for warfarin-associated acute major bleeds [2]. While fixed-dose strategies are being readily adopted for warfarin reversal, there remains a wide variety of dosing regimens utilized for Direct oral anticoagulant reversal. Cur- rently, Guideline recommendations for reversal of DOACs utilizing 4PCC is 50 units per kilogram of actual body weight with a maximum of 5000 units [4]. This recommendation mimics FDA-approved dosing strategies of warfarin reversal [3,4]. Given the lack of high quality data to define optimal dosing regimens for 4PCC, and the addition of lower quality data sets suggesting lower dosing strategies are effective for warfarin reversal, the question remains: Are lower dosing strategies also effective for DOAC reversal?

    Berger et al. examined utilizing 4PCC at a dose of 25 units per kilo- gram for reversal of DOACs in patients with intracranial hemorrhages (ICH) [5]. This was a retrospective cohort study with a primary endpoint of hemostatic effectiveness, defined as repeat neuroimaging showing stable or decreased Hematoma volume. The median dose given was 2000 units (25.9 units per kilogram) with the majority of patients (20/ 22) being reversed for factor Xa inhibitor (FXa)-associated bleeds. The primary endpoint was assessed in 19/22 patients with 94.7% (18/19) achieving hemostatic efficacy, 18.2% mortality (4/22), and a thrombo- embolic event rate of 9.1% (2/22). ICH expansion is one of the largest concerns when managing oral anticoagulant bleeds, however this study showed a high percentage of patients who achieved hemostatic effectiveness with a relatively low thromboembolic rate. A study by Schulman et al. was one of the largest studies evaluating low-dose 4PCC for FXa inhibitor-associated bleeds with 66 patients participating in this multicenter prospective cohort study [6]. Patients received a fixed dose of 2000 units and 84.8% (56/66) achieved good or moderate hemostatic efficacy. This study also had a large ICH population (54.6%), had a reported mortality rate of 14%, and 5% thrombotic complication rate. Lastly, a study by Majeed et al., evaluated 84 patients who received 1500-2000 units of 4PCC for DOAC reversal in a multicenter prospective trial [7]. A large percentage of patients received reversal for ICH (70.2%), 69.1% achieved hemostatic efficacy, and there was a 3% thrombotic rate. While this study did not show the same efficacy as previous trial, they did have a sick patient population with a mortality rate at 32%. Addi- tional studies evaluating variable dosing strategies have been described previously, including low-dose and fixed-dose options [8].

    There are multiple proposed benefits of a low-dose 4PCC option. First, lower dose options place patients at a theoretically lower risk of thromboembolic complications given that patients take DOACs because of their Hypercoagulable state. Additionally, with fewer vials to reconstitute for administration, there is a theoretical advan- tage for faster administration. Lastly, there are pharmacoeconomic considerations when evaluating low-dose options for 4PCC DOAC re- versal. The typical institutional cost of 4PCC ranges from $1.20 –

    $1.80 per unit. For an 80 kilogram patient who receives a 50 unit per kilogram dose this could range from $4800 to $7200 per regimen for DOAC reversal, compared to $2400 to $3600 for a 25 unit per ki- logram dose. Furthermore, new guidelines recommend FXa inhibi- tors over warfarin for non-valvular atrial fibrillation, increasing the potential for FXa inhibitor bleeding and placing a significant cost burden on institutions not utilizing the most cost-effective regimens for reversal [9]. Given that high quality studies for DOAC reversal with 4PCC are ongoing, there is the potential some insight may be gained from studies evaluating 4PCC for warfarin reversal. The PROPER 3 trial is an ongoing randomized controlled trial evaluating a fixed-dose 4PCC regimen of 1000 units against traditional variable dosing for warfarin reversal [10]. This trial will evaluate hemostatic efficacy in over 300 patients and is currently ongoing in The Nether- lands. This trial may ultimately help answer questions regarding fixed-dose regimens for both warfarin and DOAC reversal.

    Higher quality data is needed before a standardized drug regimen for 4PCC reversal of DOACs can be universally endorsed.

    Additionally, the question of how much data can be applied from warfarin reversal to DOAC reversal remains unanswered.

    Disclosure

    The views and opinions expressed in this article are of those of the authors and do not necessarily reflect the official policy or position of HCA Healthcare.

    Brian W. Gilbert, PharmD, BCPS, BCCCP* Emergency Medicine Clinical Pharmacy Specialist, Wesley Medical Center, Department of Pharmacy, 550 N. Hillside St, Wichita, KS 67214,

    United States of America

    * Corresponding author.

    E-mail address: [email protected] (B.W. Gilbert)

    J. Spencer Dingman, PharmD, BCCCP Neurocritical care Clinical Pharmacy Specialist, Wesley Medical Center, Department of Pharmacy, 550 N. Hillside St, Wichita, KS 67214,

    United States of America

    Jacob A. Reeder, PharmD, BCCCP Steven M. Le, PharmD, BCPS Paola J. Ponce, PharmD

    Critical Care Clinical Pharmacy Specialist, Wesley Medical Center, Department of Pharmacy, 550 N. Hillside St, Wichita, KS 67214,

    United States of America

    George J. Philip, MD, MPH Wesley Medical Center, Department of Acute Care Trauma & Surgery, 550 N. Hillside St, Wichita, KS 67214, United States of America

    Received 29 August 2019

    https://doi.org/10.1016/j.ajem.2019.158431

    References

    Yohe AS, Livings SE. Four-factor prothrombin complex concentrate dose response relationship with INR for warfarin reversal. Am J Emerg Med 2019;37(8):1534-8 Aug.

  10. Schwebach AA, Waybright RA, Johnson TJ. Fixed-dose four-factor prothrombin com- plex concentrate for vitamin K antagonist reversal: does one dose fit all? Pharmaco- therapy 2019;39(5):599-608 May.
  11. Kcentra [package insert]. Kankakee, IL: CSL Behring LLC; [August 2019].
  12. Frontera JA, Lewin 3rd JJ, Rabinstein AA. 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;24(1):6-46 Feb.
  13. Berger K, Santibanez M, Lin L, et al. A low-dose 4F-PCC protocol for DOAC-associated

    intracranial hemorrhage. J Intensive Care Med 2019. https://doi.org/10.1177/ 0885066619840992 Apr 14:885066619840992. [Epub ahead of print].

    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;118(5):842-51 May.

  14. Majeed A, Agren A, Holmstrom M, et al. Management of rivaroxaban- or apixaban associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 2017;130(15):1706-12 [Oct 12].
  15. Gilbert BW, Reeder JA, Alkhalifah MA, et al. Throwing it in reverse: an update on re- versal of oral factor Xa inhibitors. Am J Emerg Med 2019. https://doi.org/10.1016/j. ajem.2019.04.007 Apr 8. pii: S0735-6757(19)30227-X. [Epub ahead of print].
  16. Lip GYH, Banerjee A, Boriani G, et al. antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest 2018;154(5):1121-201 Nov.
  17. Abdoellakhan RA, Khorsand N, Van Hest RM, et al. Randomised controlled trial pro- tocol to evaluate a fixed dose prothrombin complex concentrate against the variable dose in vitamin K antagonist related bleeding (PROPER3). BMJ Open 2018 Mar 14;8 (3):e020764.

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