Sarode 2013: 4-Factor PCC vs FFP for VKA Reversal in Major Bleeding
In adults on a vitamin K antagonist with acute major bleeding (baseline INR ≥2.0), is 4-factor PCC (Kcentra/Beriplex P/N, INR-stratified dose, plus vitamin K 5–10 mg IV) noninferior to fresh frozen plasma (10–15 mL/kg plus vitamin K) for 24-hour hemostatic efficacy AND superior for rapid INR reduction? Phase IIIb pivotal trial that underwrote FDA approval of Kcentra (April 2013).
Sarode R, Milling TJ Jr, Refaai MA, et al. (Circulation 2013;128:1234-1243) · doi:10.1161/CIRCULATIONAHA.113.002283 · 202 patients
Population
Included
- Adults on vitamin K antagonist (warfarin or acenocoumarol)
- Acute major bleeding requiring rapid INR reversal
- Baseline INR at least 2.0
- Able to receive 4F-PCC or FFP within 5 hours of clinical presentation
- Patients 18 years of age or older receiving VKA therapy
- An elevated INR (2.0 or greater within 3 hours before study treatment)
- Experiencing an acute major bleeding event
Acute major bleeding (any of the following)
- Life-threatening or potentially life-threatening (according to the treating physician)
- Acute bleeding associated with a fall in hemoglobin of 2 g/dL or greater
- Bleeding requiring blood product transfusion
Excluded
- Use of any other coagulation product (FFP, PCC, recombinant FVIIa) within 7 days
- History of thromboembolic event within 3 months
- Severe peripheral vascular, cardiac, or cerebrovascular event within 3 months
- DIC or known severe coagulopathy unrelated to VKA
- Expected survival less than 24 hours
- Expected survival less than 3 days or surgery scheduled in less than 1 day
- Acute trauma for which reversal of VKA alone would not be expected to control bleeding
- Heparin use within 24 hours before or after enrollment
- Thrombotic or thromboembolic history within the prior 3 months (myocardial infarction, stroke, TIA, unstable angina, or severe peripheral vascular disease)
- Antiphospholipid antibody syndrome
- Suspected or confirmed sepsis
- Plasma, plasma fractions, or platelets within 2 weeks before enrollment (packed red blood cells permitted)
- Large-vessel rupture (e.g., aortic dissection or aneurysm rupture)
- Known progressive fatal disease with life expectancy less than 2 months
- Congenital or acquired coagulation factor inhibitors, hereditary protein C or protein S deficiency, or heparin-induced thrombocytopenia type II
- Use of an investigational drug within 30 days before enrollment
- Known hypersensitivity to study medication
Intracranial hemorrhage exclusions
- Glasgow Coma Scale score less than 7
- Intracerebral hematoma volume greater than 30 cm3
- Subdural hematoma thickness 10 mm or greater
- Subarachnoid hemorrhage with hydrocephalus
- Infratentorial location
- Epidural hematoma
- Intraventricular extension
- Pre-ICH modified Rankin Scale greater than 3
Source: Sarode R et al., Circulation 2013;128(11):1234-1243; PMID 23935011· Retrieved 2026-06-09
Primary Outcome (noninferiority)
Hemostatic efficacy at 24 h (effective): NI margin −10 percentage points on lower bound of 95% CI
Noninferiority design, so no superiority band is drawn: this trial tested whether one arm is not worse than the other by more than a pre-set margin, not whether it is better. Whether that margin was met is stated above.
Hemostatic efficacy at 24 h
Noninferiority established: lower bound of CI (−5.8 pp) is above the prespecified −10 pp NI margin. Sequential superiority on rapid INR reduction MET: INR ≤1.3 at 30 minutes 62.2% vs 9.6% (+52.6 pp, 95% CI 39.4–65.9; superiority declared from the CI lower bound, no p-value reported). Median infusion volume 99 mL (4F-PCC) vs 814 mL (FFP); fluid overload or similar cardiac events 4.9% vs 12.8%. Deaths through day 45 10 of 103 (9.7%) vs 5 of 109 (4.6%) and thromboembolic events 7.8% vs 6.4%; the publication reports a similar overall safety profile and was not powered for mortality. Both arms received vitamin K 5–10 mg IV; never give one without the other.
Study Arms
- Agent
- 4-factor prothrombin complex concentrate (factors II, VII, IX, X plus proteins C and S)
- Dose
- INR-stratified by factor IX content: 25 IU/kg if INR 2 to <4; 35 IU/kg if INR 4-6; 50 IU/kg if INR >6. Dose calculated on 100 kg for patients weighing more than 100 kg; maximum dose <=5000 IU of factor IX.
- Route
- IV
- Frequency
- Single intravenous dose at a maximum infusion rate of 3 IU/kg per minute
- Duration
- One-time dose (re-dose only if INR remains elevated with ongoing bleeding, per practice)
- Co-interventions
- Vitamin K by slow intravenous infusion, dosed per 2008 ACCP guidelines (5-10 mg) or local practice. Co-administration of vitamin K is required to prevent INR rebound at 12-24 h.
Dosing verbatim from Sarode R et al., Circulation 2013 (Table 2). 4F-PCC was noninferior to plasma for 24-h hemostatic efficacy (72.4% vs 65.4%; difference +7.1 pp, 95% CI -5.8 to +19.9; NI margin -10 pp) and superior for rapid INR reduction (INR <=1.3 at 30 min: 62.2% vs 9.6%; difference +52.6 pp, 95% CI 39.4-65.9). Median infusion volume 99.4 mL.
- Agent
- Plasma (fresh frozen plasma)
- Dose
- INR-stratified: 10 mL/kg if INR 2 to <4; 12 mL/kg if INR 4-6; 15 mL/kg if INR >6. Maximum dose <=1500 mL.
- Route
- IV
- Frequency
- Intravenous infusion at a study-protocol-recommended rate of 1 unit per 30-minute interval
- Duration
- Until target dose delivered
- Co-interventions
- Vitamin K by slow intravenous infusion, dosed per 2008 ACCP guidelines (5-10 mg) or local practice.
Dosing verbatim from Sarode R et al., Circulation 2013 (Table 2). Open-label phase IIIb noninferiority RCT with blinded endpoint adjudication. Median infusion volume 813.5 mL (an order-of-magnitude greater than 4F-PCC); fluid overload or similar cardiac events 12.8% vs 4.9% with 4F-PCC. Deaths through day 45: 5 of 109 (4.6%) plasma vs 10 of 103 (9.7%) 4F-PCC; thromboembolic events 6.4% vs 7.8%. The publication reports a similar overall safety profile between arms.
Safety
45-day all-cause mortality
9.7%
4.6%
Deaths through day 45 in the safety population: 10 of 103 (9.7%) 4F-PCC vs 5 of 109 (4.6%) plasma. By day 30 there were 6 vs 5 deaths; 4 further deaths occurred in the 4F-PCC arm between days 30 and 45 and none in the plasma arm. The publication describes the overall safety profile as similar between groups and the trial was not powered to detect mortality differences; 12 of the 15 deaths followed a transition to comfort care.
Fluid overload or similar cardiac events
4.9%
12.8%
Fluid overload or similar cardiac events (preferred terms: fluid overload, pulmonary edema, cardiac failure congestive, cardiac failure chronic, cardiac failure): 5 of 103 (4.9%) 4F-PCC vs 14 of 109 (12.8%) plasma. Favors 4F-PCC. Median infusion volume 99.4 mL 4F-PCC vs 813.5 mL plasma (an order-of-magnitude difference, the operational reason 4F-PCC is preferred).
Thromboembolic events through day 45
7.8%
6.4%
Any thromboembolic event: 8 of 103 (7.8%) 4F-PCC vs 7 of 109 (6.4%) FFP in the safety population. The publication reports a similar safety profile between groups.
Trial Design
Type
- Phase IIIb, multicenter, open-label, noninferiority RCT with prospective randomization
- 1:1 randomization, stratified by baseline INR and bleeding type
- Coprimary endpoints: noninferiority required on BOTH 24-h hemostatic efficacy and rapid INR reduction, then superiority tested on each; superiority was achieved only for rapid INR reduction
- NI margin -10 percentage points on lower bound of 95% CI
- Independent endpoint adjudication committee blinded to treatment
Timeline
Enrolled 2008 to 2012; assessment at 24 hours and through day 45
N
202
Enrollment
202 patients in ITT efficacy population (98 4F-PCC / 104 FFP); 216 randomized, 212 received study product. 36 sites in the United States and Europe. Enrolled 2008 to 2012. Phase IIIb multicenter open-label noninferiority RCT with prospective randomization stratified by baseline INR and bleeding type. NI margin −10 pp on lower bound of 95% CI; coprimary sequential superiority on rapid INR reduction. Independent blinded endpoint adjudication committee. 45-day follow-up. Sponsor: CSL Behring. Published Circulation 2013.
Bedside Pearl
For VKA-associated major bleeding (including ICH), give 4F-PCC 25-50 IU/kg IV (INR-stratified) plus vitamin K 10 mg IV. Goal INR <1.4 within 30 minutes. Sarode 2013 established NI on hemostasis (+7.1 pp, 95% CI -5.8 to +19.9) and superiority on INR target (62.2% vs 9.6% at 30 min). AHA/ASA 2022 Class 1, Level B-R. FFP only if 4F-PCC unavailable.