Comparison of 3-factor versus 4-factor prothrombin complex concentrate with regard to warfarin reversal, blood product use, and costs

Prothrombin complex concentrates (PCC) contain varying amounts of coagulation factors. Three-factor PCC (3F-PCC) contains minimal or no factor VII, leading to the hypothesis that it is less effective at reversing the anticoagulant effect of vitamin K antagonists. Four-factor PCC (4F-PCC) was approved in 2013 and has been recommended for reversal by the Neurocritical Care Society based on a low level of evidence. Other guidelines are not consistent in their recommendation, and there is a relative scarcity of direct comparison studies. There is a cost discrepancy; 4F-PCC is more expensive per unit, although this has the potential to be offset by a reduced dosing requirement. The aim of this study was to compare INR reversal of warfarin therapy by comparing 3- and 4F-PCC in terms of efficacy and cost.

The study was a retrospective cohort design across 2 academic institutions. Consecutive medical records between February 2014 and August 2015 were reviewed – initially 3F-PCC was part of the departmental protocol, but this was changed in early 2015 to 4F-PCC. Blood product use remained at the clinician’s discretion, and any patients missing key data were excluded. The data collected included: demographic information, indication for reversal, site of bleeding, blood product use, laboratory values, intensive care length of stay, hospital length of stay, death and any thromboembolic complications.

A total of 95 patients received PCC for warfarin, 6 were excluded for incomplete data, leaving 89 for analysis; 57 patients were treated with 3F-PCC, 32 were treated with 4F-PCC. The indication for reversal was either bleeding cessation or reversal prior to emergency surgery. The median pre-reversal INR with 3F-PCC was 2.6 (interquartile range [IQR] 2.2–3.7) and with 4F-PCC was 2.6 (IQR 2.0–3.4). Adequate reversal (subsequent INR ≤1.5) was less common with 3F-PCC, occurring in 45.6% of patients, than with 4F-PCC (87.5%)(p < 0.001). Of those patients starting with high INR values: 2 of 8 patients treated with 4F-PCC were adequately reversed when they had a starting INR ≥5; one patient with an INR of 4–6 and 2 patients with an INR of >6 received 4F-PCC, all achieved adequate reversal. There was no significant difference in either the number of patients receiving blood products, or the total volume of blood products received in either treatment group – the cost of administered blood products was not significantly different. The total median reversal cost (blood products, medications and PCC) was lower with 3F-PCC ($3663; IQR $2954–$4985) than with 4F-PCC ($5105; IQR $4082–$7524)(p = 0.001). Intensive care and hospital length of stay were not significantly different, mortality was not significantly different, and there were no recorded thromboembolic events.

In their discussion, the authors identify their key finding as 4F-PCC being more effective than 3F-PCC at reversing warfarin. This is consistent with other studies although the effect has been variable. In this case, the higher unit cost of 4F-PCC was not offset by using less, and blood product usage was also not different. The authors acknowledge the limitations of their study, conceding that their dependency on the accuracy of patient records, the small sample size, the concurrent use of plasma and variation in the use of vitamin K may have all influenced their results. Their marker for reversal as INR ≤1.5 was also somewhat arbitrary, and may not be considered adequate reversal in some centres.

This study, although small in size, adds valuable data to the question of whether there is a fundamental difference in efficacy between three-factor and four-factor PCC for the reversal of vitamin K antagonists.