Anticoagulant Reversal Handbook - Page 14

Comparison
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and small amounts of heparin . Historically , PCCs were initially developed for patients with haemophilia B , and initially was a 3F-PCC that contains factors II , IX and X but minimal factor VII levels , and which is are available in some countries . The advantage of PCCs and other factor concentrates are multiple and listed in Table 1 . They are stored at room temperature , have a long shelf life , do not require cross matching , are lyophilised and reconstituted with a small volumes for administration ( 20 – 200ml ), and undergo significant purification , so they have a minimal risk of viral transmission and TRALI .
Recommendations In clinical practice , when reversing warfarin and other VKAs with 4F-PCCs , vitamin K should also be administered concomitantly because of their long half-life of several days , potential for persistent effects , and as part of management protocols that led to their approval for warfarin reversal . 8 , 9 It should be noted that , as with reversal of any anticoagulant , there are potential prothrombotic risks because the patient was anticoagulated for a specific reason , and the risk – benefit considerations should also be considered . 11 Guidelines recommend the use of 4F-PCC for urgent VKA anticoagulation , for emergency or urgent surgery or with a life-threatening haemorrhage including intracranial haemorrhage bleed . 12 , 13 The recommendations for 4F-PCCs for warfarin reversal are based on studies that demonstrate that FFP has minimal effects on correcting PTs / INR , while PCCs will reverse warfarin , which will be subsequently reviewed in more detail .
Clinical evidence Although FFP / plasma is often transfused to patients with prolonged PT-INR , most clinicians assume that FFP will correct the coagulopathy despite the paucity of published evidence to support this practice . In a prospective audit of all FFP transfusions at a Harvard hospital over three years , patients transfused with FFP for correcting a pre-transfusion PT between 13.1 and 17 seconds ( INR 1.1 – 1.85 ) and with a follow-up PT-INR within eight hours of transfusion were evaluated . Of 1091 FFP units transfused , follow-up coagulation values within eight hours were available for 121 patients ( 324 units ). 14 FFP administration normalised
Table 1 . Advantages of factor concentrates
l Readily available for emergencies with rapid reconstitution l Can be stored at room temperature l Do not require cross matching l Relatively long shelf life l Small volumes of administration l Minimal risk of viral transmission l Undergo significant purification in pathogen removal l Facilitate administration of critical factors in high concentrations for rapid factor concentration correction l Minimal risk of transfusion-related acute lung injury or other hypersensitivity reaction
PT-INR values in only 0.8 % of patients and decreased the PT-INR value halfway to normalisation in 15 % of patients , with a median decrease in PT of 0.20 seconds and median decrease in INR of 0.07 . It had no correlation with bleeding as determined by red blood cell loss , and overall failed to correct the PT in 99 % of patients . 14
Another important concern is the need for effective acute reversal in emergency scenarios . Clinical studies including two prior randomised , smaller controlled
“ Historically , prothrombin complex concentrates were initially developed for patients with haemophilia B ”
trials of approximately 60 patients reported that PCCs reversed VKAinduced coagulopathy more rapidly than vitamin K or FFP ; however , they did not demonstrate any improvement in clinical outcomes . 15 17 In a larger registration PCC study , Sarode et al reported their prospective , non-inferiority , randomised , controlled trial evaluating a 4F-PCC ( Beriplex / Confidex / Kcentra ) with FFP for urgent reversal of warfarin / VKAs in patients with acute bleeding . 8 In this study , the primary endpoint was whether 4F-PCC was non-inferior to plasma for the co-primary end points of 24-hour haemostatic efficacy from start of infusion and INR correction of ≤1.3 at 0.5 hour after end of infusion . The intent-to-treat
efficacy population included 202 patients ( 4F-PCC , n = 98 ; plasma , n = 104 ) with mean INRs of 3.90 ( 1.8 – 20.0 range ) for the 4F-PCC group and 3.60 ( 1.9 – 38.9 ) for the plasma group . Intravenous vitamin K was administered concomitantly to all patients , and the majority of the patients (~ 60 %) presented with gastrointestinal or internal / non-visible bleeding , and ~ 10 % had intracranial haemorrhage . The median duration of PCC administration was 17 minutes in the PCC group compared with 148 minutes in the plasma group . The infusion volumes were ~ 100 ml for PCC versus ~ 813ml in the plasmatreated patients . Effective haemostasis was achieved in 72.4 % of patients receiving 4F-PCC versus 65.4 % receiving plasma , demonstrating non-inferiority ( difference , 7.1 %). However , an important and clinically relevant endpoint of rapid INR reduction was achieved in 62.2 % of 4F-PCC versus 9.6 % receiving plasma , with a similar safety profile ( adverse events ( AEs ), serious adverse events ( SAEs ), thromboembolic events , and deaths ) between groups ; 66 of 103 ( 4F-PCC group ) and 71 of 109 ( plasma group ) patients experienced ≥1 adverse event . PCC-treated patients had a lower rate of treatment-related AEs ( 9.7 %) than those given plasma ( 21.1 %). 8
In another study , Goldstein et al compared the efficacy and safety of a 4F-PCC ( Beriplex / Kcentra / Confidex ; CSL Behring , Marburg , Germany ) with plasma in VKA-treated patients needing urgent surgical or invasive procedures using dosing based on INR and weight . 9 The primary endpoint was effective haemostasis , and the co-primary endpoint was rapid INR reduction ( ≤1.3 at 0.5 hours after infusion end ). The investigators evaluated 181 patients randomised to 4F-PCC ( n = 90 ) or plasma ( n = 91 ). The intent-to-treat efficacy population included 168 patients ( 4F-PCC , n = 87 ; plasma , n = 81 ). Effective haemostasis was achieved in 78 patients ( 90 %) in the 4F-PCC group compared with 61 patients ( 75 %) in the plasma group , demonstrating both noninferiority and superiority of 4F-PCC over plasma ( difference , 14.3 %). Rapid INR reduction was achieved in 48 patients ( 55 %) in the 4F-PCC group compared with eight patients ( 10 %) in the plasma group , demonstrating both noninferiority and superiority of 4F-PCC over plasma ( difference , 45.3 %). The safety profile of 4F-PCC was similar to plasma and included 49 patients ( 56 %) receiving
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