title: Safety of a Four-factor Prothrombin Complex Concentrate Versus Plasma for Vitamin K Antagonist Reversal: An Integrated Analysis of Two Phase IIIb Clinical Trials.
abstract: OBJECTIVE
  Clinicians often need to rapidly reverse vitamin K antagonists (VKAs) in the setting of major hemorrhage or urgent need for surgery. Little is known about the safety profile of the traditional reversal agent, plasma, or the newly approved agent, four-factor prothrombin complex concentrate (4F-PCC), in a randomized setting. This is an integrated analysis of safety data from two clinical trials that evaluated 4F-PCC versus plasma for the treatment of patients requiring rapid VKA reversal for acute major bleeding or prior to an urgent surgical/invasive procedure.
  
  
  METHODS
  This descriptive analysis comprised adverse event (AE) data from two phase IIIb, randomized, controlled trials. The bleeding and surgical studies were performed across 36 and 33 sites, respectively, in nine countries, with the integrated analysis comprising 388 patients (4F-PCC, n = 191; plasma, n = 197) aged ≥ 18 years, who required VKA reversal due to major bleeding or prior to an urgent surgical/invasive procedure. Patients received either 4F-PCC, containing nonactivated factors II, VII, IX, and X and proteins C and S (Beriplex/Kcentra, CSL Behring) or plasma, both dosed according to baseline international normalized ratio and body weight. Patients were also to receive vitamin K1. AEs and serious AEs (SAEs) were assessed up to days 10 and 45, respectively.
  
  
  RESULTS
  The proportion of patients with AEs (4F-PCC, 115/191 [60.2%]; plasma, 124/197 [62.9%]) and SAEs (4F-PCC, 54/191 [28.3%]; plasma, 49/197 [24.9%]) was similar between groups. The proportion of patients with thromboembolic events was also similar between groups (4F-PCC, 14/191 [7.3%]; plasma, 14/197 [7.1%]). There were 13 (6.8%) deaths in the 4F-PCC group and 13 (6.6%) in the plasma group. Fluid overload events occurred in more patients in the plasma group than the 4F-PCC group (25 [12.7%] and 9 [4.7%], respectively).
  
  
  CONCLUSIONS
  These safety data represent the largest controlled assessment of a 4F-PCC to date. For patients requiring urgent VKA reversal, 4F-PCC had a safety profile similar to that of plasma (AEs, SAEs, thromboembolic events, and deaths), but was associated with fewer fluid overload events.
authors.affiliation: Seton Clinical Research Institute, Dell University of Texas Medical School, Dell Children's Medical Center, University Medical Center at Brackenridge, Austin, TX.
authors.forename: Truman J
authors.initials: TJ
authors.lastname: Milling
authors.affiliation: University of Rochester Medicine, Rochester, NY.
authors.forename: Majed A
authors.initials: MA
authors.lastname: Refaai
authors.affiliation: UT Southwestern Medical Center, Dallas, TX.
authors.forename: Ravi
authors.initials: R
authors.lastname: Sarode
authors.affiliation: St. Joseph Regional Health Center, Bryan, Texas A&M Health Science Center, College Station, TX.
authors.forename: Brandon
authors.initials: B
authors.lastname: Lewis
authors.affiliation: CSL Behring, King of Prussia, PA.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Mangione
authors.affiliation: CSL Behring, King of Prussia, PA.
authors.forename: Billie L
authors.initials: BL
authors.lastname: Durn
authors.affiliation: CSL Behring, King of Prussia, PA.
authors.forename: Amy
authors.initials: A
authors.lastname: Harman
authors.affiliation: UCLA School of Public Health, Los Angeles, CA.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Lee
authors.affiliation: Massachusetts General Hospital, Boston, MA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Goldstein
mesh_terms: D000368:Aged; D001779:Blood Coagulation Factors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006470:Hemorrhage / Q000188:drug therapy*; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010949:Plasma; D013923:Thromboembolism / Q000139:chemically induced; D014812:Vitamin K / Q000037:antagonists & inhibitors*
chemical_list: D001779:Blood Coagulation Factors; D014812:Vitamin K; C025667:prothrombin complex concentrates
references.citation: Thromb Res. 2004;113(6):371-8
references.pmid: 15226091
references.citation: Anesthesiology. 2008 Nov;109(5):918-26
references.pmid: 18946305
references.citation: Br J Anaesth. 2013 May;110(5):764-72
references.pmid: 23335567
references.citation: Br J Haematol. 2002 Mar;116(3):619-24
references.pmid: 11849221
references.citation: Thromb Haemost. 2011 Sep;106(3):429-38
references.pmid: 21800002
references.citation: Br J Haematol. 2011 Aug;154(3):311-24
references.pmid: 21671894
references.citation: Lancet. 2015 May 23;385(9982):2077-87
references.pmid: 25728933
references.citation: Crit Care. 2011;15(1):201
references.pmid: 21345266
references.citation: Blood Coagul Fibrinolysis. 2007 Sep;18(6):565-70
references.pmid: 17762533
references.citation: Haematologica. 2007 Feb;92(2):199-205
references.pmid: 17296569
references.citation: Arch Intern Med. 2007 Jul 9;167(13):1414-9
references.pmid: 17620536
references.citation: Transfusion. 2012 May;52 Suppl 1:65S-79S
references.pmid: 22578374
references.citation: N Engl J Med. 2011 Nov 24;365(21):2002-12
references.pmid: 22111719
references.citation: Ann Emerg Med. 2016 Jan;67(1):96-105.e5
references.pmid: 26094105
references.citation: Transfusion. 2015 Nov;55(11):2722-9
references.pmid: 26135740
references.citation: J Thromb Haemost. 2008 Apr;6(4):622-31
references.pmid: 18208533
references.citation: Chest. 2012 Feb;141(2 Suppl):e152S-e184S
references.pmid: 22315259
references.citation: Circulation. 2013 Sep 10;128(11):1234-43
references.pmid: 23935011
references.citation: Br J Haematol. 2013 Nov;163(3):303-14
references.pmid: 24032719
references.citation: Crit Care. 2013 Apr 19;17(2):R76
references.pmid: 23601765
references.citation: Transfusion. 2011 Feb;51(2):338-43
references.pmid: 20723173
references.citation: Circulation. 2013 Jul 23;128(4):360-4
references.pmid: 23770745
references.citation: Eur J Anaesthesiol. 2013 Jun;30(6):270-382
references.pmid: 23656742
references.citation: Chest. 2012 Feb;141(2 Suppl):e44S-e88S
references.pmid: 22315269
references.citation: Chest. 2008 Jun;133(6 Suppl):160S-198S
references.pmid: 18574265
references.citation: Clinicoecon Outcomes Res. 2013 Jun 26;5:289-96
references.pmid: 23836999
references.citation: Vox Sang. 2010 Oct;99(3):251-60
references.pmid: 20840339
references.citation: Arch Intern Med. 2012 Oct 22;172(19):1484-91
references.pmid: 22987143