Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal: A systematic review and meta-analysis

Major bleeding is the predominant risk of warfarin and other vitamin K antagonists – occurring at a rate of 2.3–3.0% per year, with an 11–13% mortality rate when it does occur. Rapid, effective anticoagulation reversal is an important way to reduce morbidity and mortality in this situation; this can be achieved by vitamin K and coagulation factor replacement – either FFP or PCC. FFP requires compatibility testing, and has the potential for adverse events linked to transfusion risk. PCC has less volume, no requirement for ABO compatibility and a lower risk of transfusion-related acute lung injury; however, it is more expensive and less widely available. There is no international consensus on which is the more efficacious therapy, so this meta-analysis sought to establish whether there was a demonstrable mortality benefit.

The authors conducted a literature review, using the primary outcome of all-cause mortality at 30 days. The risk of bias and overall quality of studies were assessed, and pooled odds ratios (OR) were calculated from all available data. There were eight observational studies and five randomised controlled trials (RCT) included.

The risk of bias was assessed as high in all RCTs, as they were open label, did not describe sequence generation and allocation methods adequately, had inadequate reporting of clinically relevant outcomes, or were of small sample size. The observational studies were judged to be at moderate (n = 6) or severe (n = 2) risk of bias overall.

Death within 30-days of administration occurred in 282 of 1,123 (25.1%) of patients given PCC, and 239 of 831 (28.8%) of patients given FFP. This represents a significant reduction in all-cause mortality – OR 0.56 (95% CI: 0.37–0.84; p = 0.006). The absolute risk reduction for death was 3.65%, and number needed to treat to prevent one death was 28. Most secondary outcomes are summarised in Table 1, with the exception of mean difference in time to INR correction, which was 6.50 hours less with PCC (measured in six studies; 95% CI: -9.75 to -3.24 hours, p < 0.001).

Table 1. Summary of secondary outcomes.

A significant reduction in post-infusion volume overload was observed with PCC (OR 0.27; 95% CI: 0.13–0.58, p < 0.001), whilst there was no significant difference in incidence of thromboembolic events.

In their discussion, the authors examined their findings in the context of the literature. The current Cochrane review by Johansen et al. analysed 4 RCTs and did not demonstrate a significant difference between PCC and FFP. The authors acknowledge that the benefit in their study was driven by the observational studies – a trend was evident from RCT analysis alone, but there were insufficient numbers to meet significance.

This meta-analysis demonstrates a benefit for PCC over FFP, but also highlights the relative scarcity of good quality evidence currently available.