Anticoagulant Reversal Handbook - Page 22

Acute bleeding
Table 1 . Key clinical trial data
Trial identifier
Study type / treatment arms
Patient population / sample size
Efficacy outcomes of 4F-PCC vs
comparator
Adverse events of 4F-PCC vs comparator
NCT02557672
Open-label , Phase IV 4F-PCC vs plasma
Patients undergoing elective cardiopulmonary bypass with microvascular bleeding and factor-mediated coagulopathy n = 100
Not recruiting yet ; data not available
Not recruiting yet ; data not available
NCT00928915 ( Steiner 2016 )
Open-label , Phase IV 4F-PCC vs plasma
Patients with intracranial bleeding on VKAs n = 54
INR reduction a : 67 % vs 9 % ( P = 0.0003 )
Deaths : 19 % vs 35 %
NCT00708435 ( Sarode 2013 )
Open-label , non-inferiority Phase III 4F-PCC vs plasma
Non-surgical patients with acute major bleeding on VKAs n = 216
Effective haemostasis b : 72 % vs 65 % ( non-inferior ) INR reduction c : 62 % vs 9.6 % ( non-inferior )
AEs : 64 % vs 65 % SAEs : 1.9 % vs . 3.7 % TEEs : 8 % vs 6 % Fluid overload or similar cardiac event : 5 % vs 13 %
NCT00803101 ( Goldstein 2015 )
Open-label , non-inferiority , Phase IIIb 4F-PCC vs plasma
Patients on VKAs who require emergency surgery n = 181
Effective haemostasis b : 90 % vs 75 % ( superior ) INR reduction c : 55 % vs 10 % ( superior )
AEs : 56 % vs 60 % TEEs : 7 % vs 8 % Fluid overload or similar cardiac event : 3 % vs 13 %
NCT02319460
Observational 4F-PCC vs plasma
Patients with acute major bleeding on VKAs n = 3450
Ongoing ; data not available
Ongoing ; data not available
NCT02429453
Open-label , Phase III trial 4F-PCC vs plasma
Patients with traumatic and spontaneous intracranial haemorrhage on VKAs n = 30
Ongoing ; data not available
Ongoing ; data not available
NCT02463591
Phase II 4F-PCC vs placebo
Healthy volunteers administered dabigatran n = 12
Ongoing ; data not available
Ongoing ; data not available
NCT02270918 ( Nagalla 2016 )
Open-label , Phase I 4F-PCC vs placebo
Healthy volunteers administered apixaban n = 12
Peak thrombin generation d : 76 % increase vs . placebo ( p = 0.025 )
No SAEs or deaths reported .
NCT02047565 ( Zahir 2015 )
Phase I 4F-PCC vs placebo
Healthy volunteers administered edoxaban n = 110
Bleeding duration d : 11.5 vs 14.7 for 50IU / kg of 4F-PCC Bleeding volume d : 2.45 vs 3.08 for 50IU / kg 4F-PCC
No SAEs , deaths or TEEs reported .
a
Defined as ≤1.2 at 3 hours after the initiation of the infusion . b
Assessed over a 24-hour period from the start of the infusion . c
Defined as ≤1.3 at 30min after the end of the infusion . d
Measured 30 minutes after the infusion . 4F-PCC : 4-factor prothrombin complex concentrate ; AEs : adverse events ; SAEs : serious adverse events ; TTEs : thromboembolic events ; VKAs : vitamin K antagonists .
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While treatment with FFP and history of congestive heart failure and kidney disease were significantly associated with volume overload in a multivariate analysis , past or current coronary artery disease , use of red blood cells , and age or gender did not influence the occurrence of cardiopulmonary overload . 17
The inherent risk of thromboembolic events ( including acute myocardial infarction , arterial and venous thrombosis and pulmonary embolism ) in patients treated with PCCs for VKA reversal is generally low but does require close monitoring . A post hoc pooled analysis of safety data from the two registration Phase III trials comparing rapid reversal of warfarin anticoagulation with 4F-PCC and FFP showed no difference in the
incidence of thromboembolic events or mortality rates for the two approaches . 18 4F-PCC has not been tested specifically in patients with a prior thrombotic or thromboembolic event within three months of treatment as these patients were excluded from the clinical trials . 13
A more recent study investigated the effectiveness of 4F-PCC compared with that of FFP in the control of ICH due to VKA use . The study was terminated due to safety concerns about the continued use of FFP , as there was far more haematoma expansion in that group compared with the 4F-PCC group . The data also showed that 4F-PPC was more effective than FFP in normalising INR . 19 A large post-marketing , observational study is currently ongoing to assess the risk of
thromboembolic events in patients treated with 4F-PCC or FFP as a result of acute major bleeding due to VKA therapy ( Table 1 ).
The agent is also being tested in patients undergoing cardiopulmonary bypass and specifically for the treatment of spontaneous or traumatic ICH . There is potential for use in the reversal of non-vitamin K antagonist oral anticoagulants ( NOACs ) as well . NOACs present important advantages relative to traditional VKAs , namely a more rapid onset of action , simpler dosing schedule , shorter half-life and reduced interactions with food . NOACs present similar rates of major bleeding as warfarin , but they seem to be associated with increased gastrointestinal bleeding , though less
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