Benefits and harms of 4-factor prothrombin complex concentrate for reversal of vitamin K antagonist associated bleeding: a systematic review and meta-analysis.

Prothrombin complex concentrate (PCC) is used for reversal of vitamin K antagonists (VKA) in patients with bleeding complications. This study aims to assess benefits and harms of 4-factor PCC compared to fresh frozen plasma (FFP) or no treatment in VKA associated bleeding. PubMed, EMBASE and CENTRAL were searched from 1945 to August 2015. Studies reporting 4-factor PCC use for VKA associated bleeding and providing data on INR normalization, mortality or thromboembolic (TE) complications were eligible. Two authors screened titles and full articles for inclusion, extracted data, and assessed risk of bias. Mortality data were pooled using Mantel-Haenszel random effects meta-analysis. Nineteen studies were included (N = 2878); 18 cohort studies and one RCT. Six studies had good methodological quality, 9 moderate and 4 poor. Baseline INR values ranged from 2.2 to >20. The INR within 1 h after PCC administration ranged from 1.4 to 1.9, and after FFP administration from 2.2 to 12. PCC reduced the time to reach INR correction in comparison with FFP or no treatment. The observed mortality rate ranged from 0 to 43% (mean 17%) in the PCC, 4.8-54% (mean 16%) in the FFP and 23-69% (mean 51%) in the no treatment group. Meta-analysis of mortality data resulted in an OR of 0.64 (95% confidence interval [CI] 0.27-1.5) for PCC versus FFP and an OR 0.41 (95% CI 0.13-1.3) for PCC versus no treatment. TE complications were observed in 0-18% (mean 2.5%) of PCC and in 6.4% of FFP recipients. Four-factor PCC is an effective and safe option in reversal of VKA bleeding events.