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evident
Original paper
2013CirculationEmergency Medicine

Sarode 4F-PCC

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

RCTAnticoagulant reversal

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Overview

Four-factor PCC was noninferior to plasma for 24-hour hemostasis and superior for rapid INR correction in VKA-associated major bleeding.

Clinical takeaway

Four-factor PCC reverses vitamin K antagonist-associated major bleeding at least as well as plasma and corrects the INR much faster.

Key result

Effective hemostasis occurred in 72.4% with 4F-PCC vs 65.4% with plasma (difference 7.1%; 95% CI -5.8 to 19.9); INR of 1.3 or less at 0.5 hour was 62.2% vs 9.6%.

Practice impact

Prefer 4F-PCC over plasma when a patient on a vitamin K antagonist has major bleeding that needs urgent reversal.

Evidence

Study design

Phase IIIb, multicenter, open-label, plasma-controlled, noninferiority trial.

Enrollment

202

Follow-up

Hemostatic efficacy assessed at 24 hours from the start of infusion; INR at 0.5 hour after the end of infusion.

Geography

Not listed

Clinical question

Is 4-factor prothrombin complex concentrate noninferior to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding?

Population

  • Nonsurgical patients on vitamin K antagonists presenting with major bleeding.

Intervention

Nonactivated 4-factor prothrombin complex concentrate containing factors II, VII, IX, and X and proteins C and S.

Comparator

Plasma.

Primary outcome

Coprimary end points of 24-hour hemostatic efficacy from the start of infusion and INR correction to 1.3 or less at 0.5 hour after the end of infusion.

4F-PCC was noninferior to plasma for 24-hour hemostasis and superior for rapid INR correction.

Risk difference / 7.1 / 95% CI -5.8 to 19.9

Key results

  • Effective hemostasis occurred in 72.4% with 4F-PCC vs 65.4% with plasma (difference 7.1%; 95% CI -5.8 to 19.9), meeting noninferiority.
  • INR of 1.3 or less at 0.5 hour occurred in 62.2% with 4F-PCC vs 9.6% with plasma (difference 52.6%; 95% CI 39.4-65.9), meeting superiority.
  • Median baseline INR was 3.90 in the 4F-PCC group and 3.60 in the plasma group.
  • Assessed coagulation factors were higher with 4F-PCC from 0.5 to 3 hours after infusion start (p<0.02).

Harms

  • Adverse events, serious adverse events, thromboembolic events, and deaths were similar between groups.
  • At least one adverse event occurred in 66 of 103 patients receiving 4F-PCC and 71 of 109 receiving plasma.

Clinical Use

Practice impact

  • Prefer 4F-PCC over plasma when a patient on a vitamin K antagonist has major bleeding that needs urgent reversal.

Applicability

  • Most applicable to nonsurgical patients with vitamin K antagonist-associated major bleeding who need urgent reversal.

Limitations

  • This is vitamin K antagonist major bleeding, not factor Xa inhibitor reversal.
  • The trial was open-label and excluded surgical patients.
  • Clinical hemostasis was noninferior, not proven superior; the large difference was laboratory INR correction.

Common misinterpretations

  • Faster INR correction is not the same as proven superior bleeding control.
  • Do not use this trial to choose reversal for direct oral anticoagulants.

Related evidence

ANNEXA-I - Similar Question

Citation

Sarode R, Milling TJ Jr, Refaai MA, et al. 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;128(11):1234-1243. doi:10.1161/CIRCULATIONAHA.113.002283

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.