Michael P Gulseth Anticoagulation Consulting, Inc.
|Posted by gulseth.michael on June 20, 2018 at 5:25 PM|
By Darren R Kueter, Student Pharmacist
Edited by Michael P. Gulseth, Pharm. D., BCPS, FASHP
PCC (prothrombin complex concentrate) is a reversal agent that can be utilized in the event of acute major bleeding or the need for urgent surgery in patients that are taking vitamin K antagonists such as warfarin. PCC does have many advantages over FFP (fresh frozen plasma) for the reversal of bleeding events. These advantages include quicker reconstitution (no thawing needed), a smaller volume of product needed, and lack of need for blood group typing. One challenge that PCC presents to clinicians is that dosing is dependent on the patient’s pre-dose INR and the patient’s body weight when reversing warfarin, per the package labeling based on the phase III trials. (1) Due to this, calculating dosing of PCC is challenging in acute life-threatening situations. Thus, some clinicians have been investigating using fixed doses of PCC for all patients to make this process much less complicated and speed delivery of product. Some data does support fixed-dose PCC for the reversal of VKA associated bleeding, but the specific fixed dose of PCC, specific patient bleeding situations, the specific PCC product used and time to reversal differ from study to study which makes the results difficult compare.
Current FDA Approved Dosing (1) :
INR 2 to <4 = 25 units/kg (max of 2500 units)
INR 4 to 6 = 35 units/kg (max of 3500 units)
INR >6 50 units/kg (max of 5000 units)
Available Vial sizes:
Data to evaluate the effectiveness of fixed-dose PCC:
Abdoellakhan et al. Fixed Versus Variable Dosing of Prothrombin Complex Concentrate in Vitamin K Antagonist-Related Intracranial Hemorrhage: A Retrospective Analysis (2) :
Retrospective study using Cofact (Cofact is very similar to Kcentra (contains clotting factors 2, 7, 9 and 10 but does not contain proteins C and S like Kcentra))
• Looked at the successful achievement of an INR less than equal to 1.5 with a fixed vs variable dosing strategy for PCC in patients with ICH due to VKA therapy.
• The two treatment arms were fixed dose PCC with a dose of 1000 IU ( n=28 and variable dose PCC with a median dose of 1750 IU (n=25).
• 68% of the patients in the fixed dose treatment arm achieved an INR less than equal to 1.5, while 96% of the patients in the variable dose treatment arm achieved an INR less than equal to 1.5 (p=0.01).
Astrup et al. Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis (3) :
• Retrospective analysis using Kcentra at a fixed dose of 1500 IU.
• Looked at how many of the total of 37 patients achieved an INR less than equal to 1.5 after a single dose of 4FPCC (Kcentra) and how many of the patients achieved an INR less than equal to 2 after a single dose of 4FPCC (Kcentra).
• Two of the patient’s in this study had pre-treatment INRs of less than equal to 1.5 and were not included in the efficacy analysis. 74% (n=26) of patients achieved an INR less than equal to 1.5.
• Seven of the patient’s in this study had pre-treatment INRs of < 2 and were not included in the efficacy analysis. 100% (n=30) of patients achieved an INR < 2.
• No thrombotic events were reported within 7 days of the administration of 4FPCC (Kcentra) in these patients.
Klein et al. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal (4) :
• Retrospective study using Kcentra at a fixed dose of 1500 IU.
• Looked at how many of the total of 39 patients achieved an INR <2 and how many of them achieved an INR < 1.5 after reversal with 4FPCC.
• 92.3% (n=36) of patients reached the goal INR <2 after reversal with 4FPCC, and 71.8% ( n=28 of patients reached the goal INR <1.5 after reversal with 4FPCC.
• No thrombotic events were reported in the 7 days following reversal with 4FPCC (Kcentra) in these patients.
Khorsand et al. An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies (5) :
• Observational prospective study using Cofact to assess the non-inferiority of fixed-dose PCC (n=101) when compared to variable-dose PCC (n=139).
• Looked at the number of patients that reached an INR of < 2 after PCC treatment and the number of patients that reached a successful clinical outcome after PCC treatment.
• The fixed-dose group received 1040 UI F IX and the variable dose group received a median dose of 1560 UI F IX.
• 92% of the patients in the fixed-dose group reached an INR of <2, while 95% of the patients in the variable-dose group reached an INR of <2 after treatment with PCC. Risk difference -2.99% (90% CI -8.6 to 2.7). Fixed dose not found to be non-inferior.
• 96% of the patients in the fixed-dose group had a successful clinical outcome, while 88% of the variable-dose group had a successful clinical outcome. Risk difference 8.3% (90% CI 2.7 to 13.9). Fixed dose found to be non-inferior.
This data seems to suggest that fixed doses of PCC around 1500 units have a good mix of efficacy and safety while fully acknowledging this is not well-controlled data. Despite the relatively small amount of data available, the American College of Cardiology (ACC) has supported a fixed dose of PCC. (6) In their decision pathway for the management of bleeding in patients on oral anticoagulants, the ACC suggests administering 1000 units for any major bleed and 1500 units for intracranial hemorrhage. This sets up the following questions:
1. We are curious at what other facilities are doing out there. Are you using fixed doses?
2. If fixed dose is used, is it used for warfarin only or off-label for DOAC reversal?
3. Will the manufacturer create 1500 unit vial size? You would think this would be a market opportunity for them, but want to hear others thoughts.
Please comment below.
1. CSL Behring. Kcentra (Prothrombin Complex Concentrate, Human) prescribing information. www.kcentra.com/prescribing-information. Accessed May 23, 2018.
2. Abdoellakhan RA, Miah IP, Khorsand N, Meijer K, Jellema K. Fixed Versus Variable Dosing of Prothrombin Complex Concentrate in Vitamin K Antagonist-Related Intracranial Hemorrhage: A Retrospective Analysis. Neurocritical care. Feb 2017;26(1):64-69.
3. Astrup, G., Sarangarm, P. & Burnett, A. Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis. Journal of Thrombosis and Thrombolysis. 2018 45: 300.
4. Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. The American journal of emergency medicine. Sep 2015;33(9):1213-1218.
5. Khorsand N, Veeger NJ, van Hest RM, Ypma PF, Heidt J, Meijer K. An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies. Haematologica. Oct 2012;97(10):1501-1506.
6. Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants. Journal of the American College of Cardiology. Dec 2017; 1-26.