When patients receiving the anticoagulant warfarin experience a major bleeding event or have to undergo emergency surgery, they need rapid and effective reversal of warfarin's anticoagulant effect. However, there is no consensus about the optimal strategy for reversal, the most common being coagulation factor replacement therapy with prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP).
In a systematic literature review published in the Journal of Thrombosis and Haemostasis, Chatree Chai-Adisaksopha, PhD, of the Department of Medicine at McMaster University in Canada, and authors analyzed 13 studies investigating the efficacy and safety of PCCs or FFP for warfarin reversal, finding that reversal with PCC was associated with a significant reduction in all-cause mortality (odds ratio [OR] = 0.56; 95% CI 0.37-0.84; p=0.006) and better performance on other secondary outcomes compared with FFP.
"The goals of reversal treatment are to restore hemostasis, stop further bleeding, and reduce bleed-related morbidity and mortality," Dr. Chai-Adisaksopha and authors wrote. "International consensus regarding the optimal coagulation factor replacement strategy is lacking," with British, American, French, Australian, and other clinical practice guidelines recommending different approaches.
The authors searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from inception to December 2015 and selected five randomized, controlled trials and eight observational studies for their analysis – all of which directly compared PCC (either three-factor [3F] or four-factor [4F]) with FFP. Studies were excluded if they evaluated a combination of PCCs and FFP or factor VIIa as a co-intervention.
The 13 studies included 2,114 patients; all were adults who presented with warfarin-associated major bleeding or required urgent warfarin reversal for surgery or an invasive procedure.
In the 10 studies (comprising 1,123 patients) that reported on mortality, the study's primary endpoint, more deaths occurred in patients treated with FFP than with PCCs (28.76% [n=239] vs. 25.11% [n=282]; p value not provided). An a priori subgroup analysis also found that PCCs significantly reduced all-cause mortality compared with FFPs (OR=0.57; 95% CI 0.37-0.9; p=0.02). In addition, 4F-PCCs were associated with reduced all-cause mortality, compared with FFP (OR=0.53; 95% CI 0.34-0.83; p=0.005); however, 3F-PCCs were not (OR=3.55; 95% CI 0.12-105.82; p=0.47).
Patients who received reversal with PCC also had a greater likelihood of achieving clinical hemostasis (a secondary endpoint) in the two studies that reported on this outcome: 77.2 percent of patients (n=149/193) who received PCC achieved hemostasis, compared with 64.5 percent (n=129/200) of those who received FFP (OR=2; 95% CI 0.85-4.68; p=0.11).
In the six studies that assessed the likelihood of achieving normalization of international normalized ratio (INR), Dr. Chai-Adisaksopha and authors found that 60.62 percent of PCC-treated patients (n=157/259) had rapid INR reduction, compared with 12.78 percent of FFP-treated patients (n=34/266), for an OR of 10.8 (95% CI 6.12-19.07; p<0.001). Further, the time to INR correction and the mean difference of INR correction was âˆ’6.5 hours in favor of PCC (95% CI âˆ’9.7 to âˆ’3.24; p<0.001).
Rates of red blood cell (RBC) transfusion were similar for patients receiving FFP compared with patients who received PCC, according to the results of four studies that reported on this endpoint: 27.1 percent (n=100/369) versus 24.6 percent (n=93/378; OR=0.88; 95% CI 0.53-1.43; p=0.6).
In two secondary safety outcomes that were also measured, PCC was associated with a lower incidence of post-transfusion congestive heart failure or volume overload (OR=0.27; 95% CI 0.13-0.58; p<0.001), but not a significant reduction in thromboembolism risk (OR=0.91; 95% CI 0.44-1.89; p=0.81).
The authors noted, though, that "the study may have been underpowered to detect a difference in this outcome."
"Administration of PCC was associated with reduced all-cause mortality, increased likelihood of INR normalization, shortened time to INR correction, and reduced volume overload compared to FFP," Dr. Chai-Adisaksopha and authors concluded. Taking into account that "the use of FFP is associated with prolonged administration time, transfusion-associated volume overload and transfusion-related acute lung injury," these findings suggest that PCC is preferable to FFP for patients needing urgent warfarin reversal.
The study is limited by the heterogeneity and retrospective nature of the study design, patient population, indication for reversal, reversal protocol, and outcome reporting.
Chai-Adisaksopha C, Hillis C, Siegal DM, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal: A systematic review and meta-analysis. Thromb Haemost. 2016;116:879-890.