Assessed coagulation reasons were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start ((n=98)(n=104)value for noninferiority (n=104)value for noninferiority em P /em 0.0001 rejecting null hypothesis of inferiority of 4F-PCC; 4F-PCC superior to plasma: lower limit of 95% CI 0. Individuals in the 4F-PCC group achieved INR correction more rapidly than those in the plasma group; 1 hour after the start of infusion, 68 individuals (69%) in the 4F-PCC group experienced an INR 1.3 compared with none in the plasma group. (1.8C20.0) for the 4F-PCC group and 3.60 (1.9C38.9) for the plasma group. Effective hemostasis was accomplished in 72.4% of individuals receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, ?5.8 to 19.9]). Quick international normalized percentage reduction was accomplished in 62.2% of individuals receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC NMDI14 superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start ((n=98)(n=104)value for noninferiority (n=104)value for noninferiority em P /em 0.0001 rejecting null hypothesis of inferiority of 4F-PCC; 4F-PCC superior to plasma: lower limit of 95% CI 0. Individuals in the 4F-PCC group accomplished INR correction more rapidly than those in the plasma group; 1 hour after the start of infusion, 68 individuals (69%) in the 4F-PCC group experienced an INR 1.3 compared with none in the plasma group. This tendency continued at the subsequent time points and was still obvious at 24 hours after start of infusion (88% versus 58%, respectively; Number 2A). Furthermore, median INR was significantly reduced the 4F-PCC group compared with the plasma group until 12 hours after the start of infusion (Number 2B). Open in a separate window Number 2. A, Time to international normalized percentage (INR) correction (intention-to-treat efficacy human population). B, Median INR by time point (intentionto-treat effectiveness human population). 4F-PCC shows 4-element prothrombin complex concentrate; and IQR, interquartile range. Inside NMDI14 a post hoc analysis, the 97.5% Farrington-Manning risk difference CIs for hemostatic efficacy and rapid INR reduction NMDI14 were also calculated with the assumption the noninferiority boundary was ?10%. These 97.5% CIs are equivalent to testing each of the 2 end points at individual 1-sided levels of =0.0125. In this way, the multiplicity of screening for superiority in 2 coprimary end points was tackled with preservation of the type I error of a 0.025 significance level. For hemostatic effectiveness, the 97.5% CI was ?7.6% to 21.7%. For quick INR reduction, the 97.5% CI was 37.5% to 67.7%. The lower bound of this CI is greater than zero, and therefore superiority can be declared for 4F-PCC for the quick INR reduction end point. Coagulation Element/Protein Levels Mean preinfusion levels of VKDFs, protein C, and protein S were similar between organizations ( em P /em 0.05). Number 3 shows changes in factor levels over time. Mean factor levels were significantly higher in the 4F-PCC group than the plasma group at 0.5, 1, 3, and 6 hours ( em P /em 0.05) apart from factor VII at 6 hours (not NMDI14 significantly different between groups; em P /em =0.19). Open in a separate window Number 3. Mean coagulation protein levels before and after infusion (intention-to-treat effectiveness human population). 4F-PCC shows 4-element prothrombin complex concentrate; F, factor; Personal computer, protein C; and PS, protein S. Results were related for the coprimary end points when analyzed by country/region (Furniture VII and VIII in the online-only Data Product). Similar results were also seen for the ITT (Furniture IX and X in the online-only Data Product) and per protocol populations (data not shown). Safety Security outcomes were assessed with the use of the ITT-S human population (Number 1). There were 66 of 103 individuals in the 4F-PCC group and 71 of 109 individuals in the plasma group with 1 AE (Table 8). AEs regarded as by investigators to be treatment related were reported for 10 individuals in the 4F-PCC group and 23 in the plasma group. Severe AEs were NMDI14 reported for 32 individuals in the 4F-PCC group and 26 in the plasma group, of which 2 (ischemic stroke, deep vein thrombosis in the 4F-PCC group) and 4 (myocardial ischemia [n=2], respiratory failure, fluid overload in the plasma group) were regarded as treatment related by investigators (Table XI in the online-only Data Product). Table 8. Summary of AEs Itgb2 (Intention-to-Treat Security Human population) thead th align=”remaining” valign=”top” rowspan=”1″ colspan=”1″ /th th colspan=”2″ align=”center” valign=”middle” rowspan=”1″ No. (%) of Individuals hr / /th th align=”remaining” valign=”bottom” rowspan=”1″ colspan=”1″ AE /th th align=”center” valign=”middle” rowspan=”1″ colspan=”1″ 4F-PCC br / (n=103) /th th align=”center” valign=”middle” rowspan=”1″ colspan=”1″ Plasma br / (n=109) /th th colspan=”3″ align=”remaining” valign=”top” rowspan=”1″ hr / /th /thead Any nonserious AE*66 (64.1)71 (65.1)?Related AE?10 (9.7)23 (21.1)?AE leading to treatment discontinuation03 (2.8)Severe AE*32 (31.1)26 (23.9)?Related serious AE?2 (1.9)4 (3.7)AEs of interest?Deaths to day time 306 (5.8)5 (4.6)?Deaths to day time 4510 (9.7)5 (4.6)??Related deaths (to day 45)?1 (1.0)0?Thromboembolic AE8 (7.8)7 (6.4)??Related thromboembolic AE?4 (3.9)3 (2.8)?Fluid overload or related cardiac event5 (4.9)14 (12.8)??Related fluid overload or related cardiac event?07 (6.4) Open in a separate windowpane 4F-PCC indicates 4-element prothrombin complex concentrate; and AE, adverse event. *Defined in Table XIV in the online-only Data Product. ?Defined as events for which there was a relationship to study treatment in the opinion of the investigator. AEs with missing relationship were regarded as treatment related..