Fixed-dose Activated Versus Variable-dose Inactivated Prothrombin Complex Concentrate for Warfarin-associated Major Bleed

• ClinicalTrials.gov Identifier: NCT02565836
• Recruitment Status: Completed
• First Posted: October 1, 2015
• Last Update Posted: October 25, 2017
• Sponsor: Rush University Medical Center
• Collaborator: Advocate Health Care
• Information provided by (Responsible Party): Rush University Medical Center

Study Description

Brief Summary:

This study aims to assess a fixed-dose regimen of activated prothrombin complex concentrate (FEIBA VH, Baxter) versus the variable, manufacturer recommended, dose regimen of inactivated prothrombin complex concentrate (Kcentra, CSL Behring) for reversal of warfarin-associated major hemorrhage.

Condition or disease	Intervention/treatment
Hemorrhage	Drug: fixed-dose activated prothrombin complex concentrate; Drug: variable-dose inactivated prothrombin complex concentrate

Detailed Description:

Warfarin, a vitamin K antagonist (VKA), is the most frequently prescribed oral anticoagulant. Warfarin-associated major hemorrhage occurs at a rate of 1.7% to 3.4% in routine clinical practice and warrants rapid reversal of anticoagulation by correcting supratherapeutic international normalized ratio (INR) values.

Warfarin inhibits synthesis of vitamin K dependent coagulation factors II, VII, IX, and X, and strategies for reversal of warfarin-associated coagulopathy are aimed at restoring deficient factors. Four-factor prothrombin complex concentrates (PCCs) contain the coagulation factors which warfarin inhibits and are an attractive option for rapid reversal due to ease of reconstitution and no requirement for blood-type matching.

Manufacturer dosing recommendations exist for PCCs based on patient weight, baseline INR, and target INR, but studies have suggested fixed dosing strategies in an effort to determine the most efficacious dose for VKA-reversal while sparing adverse events. These studies have also utilized different PCC formulations, with some studies utilizing 4-factor activated PCC (aPCC), which denotes product containment of factor VII in an activated state.

In the United States, product availability is limited to a single 4-factor aPCC (FEIBA VH, Baxter) indicated for hemophilia patients with inhibitors and a single 4-factor inactivated PCC (Kcentra, CSL Behring) approved for VKA-reversal. Various institutions choose to utilize off-label fixed dosing strategies of 4-factor aPCC in an effort to administer the lowest possible dose to reverse VKAs, while others utilize manufacturer recommended dosing of 4-factor inactivated PCC.

Study Design

• Study Type: Observational
• Actual Enrollment: 342 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: Reversal of Warfarin-associated Major Hemorrhage: a Multicenter, Retrospective Cohort Study of Fixed-dose Activated (FEIBA VH) Versus Variable-dose Inactivated (Kcentra) Prothrombin Complex Concentrate
• Study Start Date: October 2015
• Actual Primary Completion Date: September 30, 2016
• Actual Study Completion Date: September 30, 2016

Groups and Cohorts

Group/Cohort	Intervention/treatment
fixed-dose aPCC; Patients receiving fixed-dose activated prothrombin complex concentrate (FEIBA VH) for reversal of warfarin-associated major hemorrhage.	Drug: fixed-dose activated prothrombin complex concentrate; FEIBA VH 500 units IV one time for INR less than 5. FEIBA VH 1000 units IV one time for INR greater than 5. Check INR after infusion and may repeat dose if INR still elevated; Other Names: FEIBA; FEIBA VH
variable-dose PCC; Patients receiving vairable-dose inactivated prothrombin complex concentrate (Kcentra) for reversal of warfarin-associated major hemorrhage.	Drug: variable-dose inactivated prothrombin complex concentrate; Kcentra 25 units/kg IV one time for INR less than 4. Kcentra 35 units/kg IV one-time for INR 4 to 6. Kcentra 50 units/kg IV one-time for INR greater than 6. Check INR after infusion and may repeat dose if INR still elevated.; Other Name: Kcentra

Outcome Measures

Primary Outcome Measures :

1. Achievement of INR less than or equal to 1.5 [ Time Frame: 60 minutes ]
   The number of patients achieving a goal INR of less than or equal to 1.5 within 60 minutes following administration of 4-factor fixed-dose aPCC (FEIBA VH) versus variable-dose inactivated PCC (Kcentra) for reversal of warfarin-associated major hemorrhage.

Secondary Outcome Measures :

1. Incidence of mortality or thrombotic events [ Time Frame: 30 days ]
   Incidence of mortality, deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic cerebrovascular events within 30 days following administration of 4-factor fixed-dose aPCC (FEIBA VH) or variable-dose inactivated PCC (Kcentra) for reversal of warfarin-associated major hemorrhage.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Patients administered a prothrombin complex concentrate as part of routine care for INR normalization due to a major bleed will be assessed for inclusion.

Criteria

Inclusion Criteria:

• Pre-treatment INR lab value greater than 1.5
• Receipt of treatment with a 4-factor PCC for INR normalization due to warfarin-associated major hemorrhage

Exclusion Criteria:

• Patients treated with a PCC for an urgent invasive procedure without active hemorrhage
• Patients treated with PCC not taking a VKA
• Unavailable pre- or post-treatment INR lab values
• Pregnant patients

Contacts and Locations

Sponsors and Collaborators

Rush University Medical Center

Advocate Health Care

Investigators

• Principal Investigator: Gary D Peksa, PharmD; Rush University Medical Center
• Principal Investigator: Robert Mokszycki, PharmD; Advocate Christ Medical Center

More Information

Publications:

Junagade P, Grace R, Gover P. Fixed dose prothrombin complex concentrate for the reversal of oral anticoagulation therapy. Hematology. 2007 Oct;12(5):439-40.

Wójcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med. 2009 Nov 26;2(4):217-25. doi: 10.1007/s12245-009-0125-8.

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. 2012 Oct;97(10):1501-6. doi: 10.3324/haematol.2012.063701. Epub 2012 Apr 4.

Stewart WS, Pettit H. Experiences with an activated 4-factor prothrombin complex concentrate (FEIBA) for reversal of warfarin-related bleeding. Am J Emerg Med. 2013 Aug;31(8):1251-4. doi: 10.1016/j.ajem.2013.05.008. Epub 2013 Jun 10.

Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013 Sep 10;128(11):1234-43. doi: 10.1161/CIRCULATIONAHA.113.002283. Epub 2013 Aug 9.

• Responsible Party: Rush University Medical Center
• ClinicalTrials.gov Identifier: NCT02565836 History of Changes
• Other Study ID Numbers: 15092404
• First Posted: October 1, 2015
• Last Update Posted: October 25, 2017
• Last Verified: October 2017

Keywords provided by Rush University Medical Center:

Vitamin K 1; prothrombin complex concentrates; warfarin

Additional relevant MeSH terms:

Hemorrhage; Pathologic Processes; Warfarin; Thrombin; Anti-inhibitor coagulant complex; Anticoagulants; Hemostatics; Coagulants