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Oral Anticoagulation Reversal Learning Zone

Is there a difference in efficacy, safety, and cost-effectiveness between 3-factor and 4-factor prothrombin complex concentrates among trauma patients on oral anticoagulants?

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Last updated:12th Mar 2020
Published:12th Feb 2020
This retrospective study compared 3-factor (3F) and 4-factor (4F) prothrombin complex concentrates (PCC) in 64 trauma patients requiring oral anticoagulant reversal. Both were effective at reversal and safe, however 4F-PCC was more effective at reversal, and despite being a more expensive product, was found to be more cost-effective in this setting.

Oral anticoagulation (OAC) is widely prescribed to prevent thromboembolic disease, but frequently requires urgent reversal; this has previously been accomplished with vitamin K and fresh frozen plasma (FFP). Increasingly this is being supplanted by PCC – it is faster acting, has a lower volume, and provokes negligible concern over transfusion reaction. There are currently limited data comparing 3F- and 4F-PCC, with some suggestion that 4F-PCC may be more effective at reversing OAC. 

Based in two centres in the United States, this was a retrospective study. Data were taken from the pharmacy medications database and patient records. Inclusion criteria were: trauma-related admission, pre-existing treatment with OAC, and baseline international normalised ratio (INR), on admission, of ≥1.5. 

Data collected were:

  • Demographics
  • Indication
  • Mechanism of injury
  • Severity of illness
  • Laboratory coagulation values
  • Coagulation-related medications and blood products received
  • Adverse events.

The data were stratified into two groups, those who had received 3F- and 4F-PCC. Outcomes were successful reversal of INR (a second INR measurement of <1.5), adverse events, and cost efficiency. The latter was calculated by dividing the cost of all administered doses of reversal medication and blood products by the number of successful reversals. A multivariate analysis was performed to control for all identified differences in baseline demographics.

The final analysis included 64 patients; 61 of these were on existing warfarin treatment, with three receiving rivaroxaban. For anticoagulation reversal, 46 were treated with 3F-PCC, 18 with 4F-PCC. The majority of patients included were elderly, 80% presented with a fall, and the overall demographics were similar. Atrial fibrillation was the most common indication for anticoagulation.

Table 1. Comparison of INR pre- and post-administration with PCC. Results expressed as mean ± 1 standard deviation.


There was a successful reversal in 23/46 patients (50%) given 3F-PCC, and 15/18 patients (83%) given 4F-PCC (p = 0.022). The difference was statistically significant even when the patients on rivaroxaban (n = 3) were excluded from the analysis. After multivariate logistical regression analysis of all known dosing and timing variables, 4F-PCC remained an independent predictor for successful reversal (odds ratio 5.0 [95% CI 1.2–19.6]; p = 0.021).

There were seven thromboembolic events recorded, all in the 3F-PCC group (although this was not significant), and all deep vein thrombosis. The cost analysis revealed that 4F-PCC was a more cost effective product despite being more expensive, with mean costs per reversal of $5,382 for 3F-PCC and $3,797 for 4F-PCC.

In their discussion, the authors remark upon the improved reversal rate with 4F-PCC, with no serious complications from either treatment. In the context of the literature, anticoagulated patients have worse outcomes in trauma, with evidence to suggest that a rapid reversal of anticoagulation improves this. The literature has also demonstrated a superiority of PCC over FFP, and those studies examining the same question explored here have found consistently that 4F-PCC is more effective than 3F-PCC, with similar rates of adverse events. The increase in cost-effectiveness is attributed to the greater likelihood of successful reversal, with fewer products used overall – the specific costing model for the two institutions was used, so extrapolation of these data may be limited, however they do reflect a real-world cost. This study was limited by its small scale, retrospective design, and the patient selection and treatment bias that relates to this. Due to the retrospective nature, dosing was variable, and the timing between treatment and repeat INR measurement was not standardised.

This study is consistent with the relatively limited literature to date. On its own it is too small in scale to draw meaningful conclusions; however, the application of a cost analysis provides a useful new perspective. When added to the existing evidence, it is apparent that there is growing data to suggest that 4F-PCC is more effective than 3F-PCC.