Anticoagulant Reversal Handbook - Page 15

Comparison
4F-PCC who had AEs compared with 53 patients ( 60 %) receiving plasma , and included thromboembolic AEs in 7 % of patients receiving 4F-PCC compared with 8 % of patients receiving plasma . Fluid overload or similar cardiac events were observed in 3 % versus 13 %, and late bleeding events were observed in 3 % versus 5 % for 4F-PCC versus plasma , respectively . 9
An additional analysis of these two Phase IIIb clinical trials by Milling et al included patients across 36 and 33 sites , in nine countries , comprising 388 patients ( 4F-PCC , n = 191 ; plasma , n = 197 ). The proportion of patients with AEs ( 4F-PCC , 115 / 191 ( 60.2 %); plasma , 124 / 197 ( 62.9 %)) and SAEs ( 4F-PCC , 54 / 191 ( 28.3 %); plasma , 49 / 197 ( 24.9 %)) was similar between groups . The proportion of patients with thromboembolic events was also similar between groups ( 4F-PCC , 14 / 191 ( 7.3 %); plasma , 14 / 197 ( 7.1 %)). There were 13 ( 6.8 %) deaths in the 4F-PCC group and 13 ( 6.6 %) in the plasma group . Fluid overload occurred more commonly in patients in the plasma-treated group ( 25 ( 12.7 %) compared with the 4F-PCC group of 9 ( 4.7 %)), and 4F-PCC had a safety profile for adverse events similar to that of plasma but was associated with fewer fluid overload events . 6 , 18
A consistent finding in all of the comparative studies was the side effects related to fluid overload when FFP / plasma is used for VKA reversal . An additional analysis from the two Phase IIIb clinical trials by Sarode and Goldstein was an evaluation of AEs and SAEs were prospectively captured up to days 10 and 45 , respectively . 5 The results were analysed to best determine volume overload using statistical evaluation predictors . They noted in the 388 patients reported ( 4F-PCC , n = 191 ; plasma , n = 197 ), volume overload occurred in 34 patients ( 9 %) ( 4F-PCC , n = 9 ; plasma , n = 25 ). Using univariate analyses , plasma compared with 4F-PCC , additional requirements for plasma and / or platelets , race , history of heart failure , and renal disease were associated with volume overload . Using multivariate analyses , plasma compared with 4F-PCC , heart failure and renal disease were independent volume overload predictors . In an additional analysis restricted to volume overload events recorded up to day 7 , only use of plasma compared with 4F-PCC was an independent predictor for volume overload . 5
One important perspective when evaluating patients who are bleeding or require emergency surgery or procedural interventions is that they are already destined to adverse outcomes . 19 21 Studies to determine whether any intervention including PCCs improves clinical outcomes in warfarin- or other VKAassociated bleeding may not be different due to the relatively high rate of AEs in both groups . For regulatory approval , and in facilitating these described clinical studies is the emphasis of the importance of a non-inferiority design of the trials , as these studies are exceedingly difficult to perform , evaluate emergency and other patients who are often difficult to enrol , and who are already prone to adverse outcomes based on their initial presentation . However , the ability to rapidly reverse warfarin / VKA-associated coagulopathy and bleeding in patients who present with serious bleeding , using factor concentrates that do not require cross matching , and have minimal fluid requirements for administration , offer an important therapeutic approach when time is critical , and also further support the important potential for factor concentrates in clinical practice . l
References
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