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.
BACKGROUND
Patients experiencing major bleeding while taking vitamin K antagonists require rapid vitamin K antagonist reversal. We performed a prospective clinical trial to compare nonactivated 4-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent vitamin K antagonist reversal.


RESULTS
In this phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was noninferior to plasma for the coprimary end points of 24-hour hemostatic efficacy from start of infusion and international normalized ratio correction (≤1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population comprised 202 patients (4F-PCC, n=98; plasma, n=104). Median (range) baseline international normalized ratio was 3.90 (1.8-20.0) for the 4F-PCC group and 3.60 (1.9-38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, -5.8 to 19.9]). Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (P<0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced ≥1 adverse event.


CONCLUSIONS
4F-PCC is an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of international normalized ratio and factor levels.


BACKGROUND
http://www.clinicaltrials.gov. Unique identifier: NCT00708435.
University of Texas Southwestern Medical Center, Dallas (R.S.); Seton/University of Texas Southwestern Clinical Research Institute of Austin, Dell Children's Medical Center, University Medical Center at Brackenridge, Austin, TX (T.J.M.); University of Rochester Medical Center, Rochester, NY (M.A.R.); CSL Behring LLC, King of Prussia, PA (A.M., B.L.D.); CSL Behring GmbH, Marburg, Germany (A.S.); and Massachusetts General Hospital, Boston (J.N.G.).
Ravi
R
Sarode
Truman J
TJ
Milling
Majed A
MA
Refaai
Antoinette
A
Mangione
Astrid
A
Schneider
Billie L
BL
Durn
Joshua N
JN
Goldstein
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D000931:Antidotes / Q000627:therapeutic use; D001779:Blood Coagulation Factors / Q000009:adverse effects / Q000627:therapeutic use*; D004338:Drug Combinations; D004630:Emergencies; D005164:Factor IX / Q000009:adverse effects / Q000627:therapeutic use*; D005167:Factor VII / Q000009:adverse effects / Q000627:therapeutic use*; D005170:Factor X / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D006490:Hemostatics / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010949:Plasma; D011446:Prospective Studies; D011516:Prothrombin / Q000009:adverse effects / Q000627:therapeutic use*; D016037:Single-Blind Method; D013923:Thromboembolism / Q000139:chemically induced / Q000517:prevention & control; D016896:Treatment Outcome; D014812:Vitamin K / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D000931:Antidotes; D001779:Blood Coagulation Factors; D004338:Drug Combinations; D006490:Hemostatics; C525441:factor IX, factor VII, factor X, prothrombin drug combination; D014812:Vitamin K; C025667:prothrombin complex concentrates; D005167:Factor VII; D011516:Prothrombin; D005164:Factor IX; D005170:Factor X
anticoagulants; hemorrhage; plasma; prothrombin complex concentrates; vitamin K antagonist