Three-factor versus four-factor prothrombin complex concentrate for warfarin reversal - a critical appraisal of the evidence

The Neurocritical Care Society published their first guidelines on antithrombotic reversal in intracranial haemorrhage (ICH) back in 2015. The guidelines recommended the use of PCC over fresh frozen plasma (FFP), but at the time of publication, no studies comparing 3-PCC and 4-PCC were available. The guidelines, therefore, recommend either PCC agent with low-quality evidence suggesting that 4-PCC is preferred.

Since then, seven studies comparing the efficacy of 3-PCC and 4-PCC have been published.

While these recent studies provide interesting results, their impact is limited by their small sample sizes and retrospective nature. Furthermore, the studies include a variety of patient populations such as ICH, gastrointestinal bleeding and patients requiring reversal for procedures. This creates uncertainty in interpreting results across different studies as there is limited evidence to show that different patient populations should have the same INR goal.

It remains uncertain as to what INR goal should be used, with the selection potentially influencing study results. Guidelines recommend that patients with ICH should have a target INR of ≤1.3, however, this has not been demonstrated to improve outcomes.  Five of the seven studies discussed used a slightly higher INR goal (1.4 or 1.5) and four of them observed similar results with 3-PCC and 4-PCC. Meanwhile, the study that used an INR goal of ≤1.3 saw an improved response with 4-PCC versus 3-PCC.

The retrospective and methodological deficiencies in the existing literature highlight the need to improve future research so that data capable of influencing guideline recommendations are captured. The recent study by DeAngelo et al. discussed two key limitations, the ongoing need to determine the most appropriate INR goal based on how it relates to clinical outcome and the clinical challenges of prompt follow-up INR assessments. However, when planning future studies researchers should aim to address all the identified limitations to provide clarity over the comparative efficacy of 3-PCC and 4-PCC.

This review offers a useful critical analysis of the available comparative data for 3-PCC and 4-PCC efficacy in patients requiring warfarin reversal. It highlights a number of recurring limitations across studies that should be addressed in future research.