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.


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.

Methods and 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.

Clinical trial registration url: http://www.clinicaltrials.gov. Unique identifier: NCT00708435.

Keywords: anticoagulants; hemorrhage; plasma; prothrombin complex concentrates; vitamin K antagonist.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anticoagulants / adverse effects*
  • Anticoagulants / pharmacology
  • Anticoagulants / therapeutic use
  • Antidotes / therapeutic use
  • Blood Coagulation Factors / adverse effects
  • Blood Coagulation Factors / therapeutic use*
  • Drug Combinations
  • Emergencies
  • Factor IX / adverse effects
  • Factor IX / therapeutic use*
  • Factor VII / adverse effects
  • Factor VII / therapeutic use*
  • Factor X / adverse effects
  • Factor X / therapeutic use*
  • Female
  • Hemorrhage / chemically induced
  • Hemorrhage / drug therapy*
  • Hemorrhage / prevention & control
  • Hemostatics / adverse effects
  • Hemostatics / therapeutic use*
  • Humans
  • International Normalized Ratio
  • Male
  • Middle Aged
  • Plasma
  • Prospective Studies
  • Prothrombin / adverse effects
  • Prothrombin / therapeutic use*
  • Single-Blind Method
  • Thromboembolism / chemically induced
  • Thromboembolism / prevention & control
  • Treatment Outcome
  • Vitamin K / antagonists & inhibitors*


  • Anticoagulants
  • Antidotes
  • Blood Coagulation Factors
  • Drug Combinations
  • Hemostatics
  • factor IX, factor VII, factor X, prothrombin drug combination
  • Vitamin K
  • prothrombin complex concentrates
  • Factor VII
  • Prothrombin
  • Factor IX
  • Factor X

Associated data

  • ClinicalTrials.gov/NCT00708435