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Fixed- Versus Variable-Dose Prothrombin Complex Concentrate for the Emergent Reversal of Vitamin K Antagonists: A Systematic Review and Meta-Analysis
Alwakeal, A., Maas, M. B., Naidech, A. M., Jahromi, B. S., Potts, M. B.
Critical care medicine. 2024
Abstract
OBJECTIVES Four-factor prothrombin complex concentrate (4-PCC) is recommended for rapid reversal of vitamin K antagonists (VKAs) such as warfarin, yet optimal dosing remains uncertain. DATA SOURCES A systematic review was conducted of PubMed, Embase, and Ovid MEDLINE (Wolters Kluwer) databases from January 2000 to August 2023 for clinical studies comparing fixed- vs. variable-dose 4-PCC for emergent VKA reversal with at least one reported clinical outcome. STUDY SELECTION Abstracts and full texts were assessed independently and in duplicate by two reviewers. DATA EXTRACTION Data were extracted independently and in duplicate by two reviewers using predefined extraction forms. DATA SYNTHESIS The analysis comprised three randomized trials and 16 cohort studies comprising a total of 323 participants in randomized trials (161 in fixed dosage and 162 in variable dosage) and 1912 patients in cohort studies (858 in fixed-dose and 1054 in variable dose). Extracranial bleeding was the predominant indication, while intracranial hemorrhage varied. Overall, a fixed-dose regimen may be associated with a lower dose of 4-PCC and results in a reduction in 4-PCC administration time compared with a variable-dose regimen. A fixed-dose regimen also likely results in increased clinical hemostasis. While there is no clear difference between the two regimens in terms of achieving a goal international normalized ratio (INR) less than 2, a fixed-dose regimen is less likely to achieve a goal INR less than 1.5. High certainty evidence indicates that the fixed-dose regimen reduces both mortality and the occurrence of thromboembolic events. Additional subgroup analyses provides exploratory data to guide future studies. CONCLUSIONS A fixed-dose regimen for 4-PCC administration provides benefits over a variable-dose regimen in terms of dose reduction, faster administration time, improved clinical hemostasis, and reduced mortality and thromboembolic events. Further studies are warranted to better refine the optimal fixed-dose regimen.
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The administration of four-factor prothrombin complex concentrate exacerbates thrombin generation in trauma patients at risk of massive transfusion: an ancillary study of the PROCOAG trial
Greze, J., Marlu, R., Baud, M., Seyve, L., Gauss, T., Bouzat, P.
Critical care (London, England). 2024;28(1):51
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Safety and efficacy of fixed versus variable-dose prothrombin complex concentrate for emergent reversal of vitamin K antagonists: A systematic review and meta-analysis
Condeni, M. S., Weant, K. A., Neyens, R. R., Eriksson, E. A., Miano, T. A.
The American journal of emergency medicine. 2023;77:91-105
Abstract
STUDY OBJECTIVE Four-factor prothrombin complex concentrate (4F-PCC) is standard of care for emergent vitamin K antagonist (VKA) reversal but optimal dosing is uncertain. This meta-analysis estimated the proportion of patients treated with fixed dose (FD) 4F-PCC who achieved adequate reversal and compared safety and efficacy of FD versus weight-based dose (WB) strategies. METHODS This review was conducted according to PRISMA guidelines. Medline and Scopus were searched and included studies evaluating FD regimens and comparing FD and WB for emergent VKA reversal. Data was pooled using random effects. Subgroup analyses examined heterogeneity. Risk of bias was assessed with Newcastle-Ottawa Scale and RoB2 score. RESULTS Twenty-three studies (n = 2055) were included with twelve (n = 1143) comparing FD versus WB. The proportion of patients achieving goal INR with FD varied depending on the INR target, being significantly higher for INR <2 (90.9%, 95% Confidence Interval (CI) 87.2, 94.06) compared to INR <1.6 (70.97%, 95%CI 65.33, 76.31). Compared to WB, FD was less likely to achieve a goal INR <1.6 (Risk Difference (RD) -13%, 95% CI -21, -4) but achieved similar reversal for a goal INR <2.0, (RD -1%, 95%CI -7, 4). There was no difference in hospital mortality (RD 4%, 95%CI -2, 9) or thrombosis (RD 0.0%, 95%CI -3, 3). CONCLUSION FD VKA reversal was associated with significantly lower attainment of goal INR compared to WB with lower INR targets. This did not translate to differences in hospital mortality, but these results should be interpreted cautiously in light of the observational nature of the included studies.
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Efficacy and Safety of Prothrombin Complex Concentrates in Liver Transplantation: Evidence from Observational Studies
Punzo, G., Di Franco, V., Perilli, V., Sacco, T., Sollazzi, L., Aceto, P.
Journal of clinical medicine. 2023;12(11)
Abstract
The risk/benefit ratio of using prothrombin complex concentrates (PCCs) to correct coagulation defects in patients with end-stage liver disease is still unclear. The primary aim of this review was to assess the clinical effectiveness of PCCs in reducing transfusion requirements in patients undergoing liver transplantation (LT). This systematic review of non-randomized clinical trials was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was previously registered (PROSPEROCRD42022357627). The primary outcome was the mean number of transfused units for each blood product, including red blood cells (RBCs), fresh frozen plasma, platelets, and cryoprecipitate. Secondary outcomes included the incidence of arterial thrombosis, acute kidney injury, and haemodialysis, and hospital and intensive care unit length of stay. There were 638 patients from 4 studies considered for meta-analysis. PCC use did not affect blood product transfusions. Sensitivity analysis, including only four-factor PCC, showed a significant reduction of RBC effect size (MD: 2.06; 95%CI: 1.27-2.84) with no true heterogeneity. No significant differences in secondary outcomes were detected. Preliminary evidence indicated a lack of PCC efficacy in reducing blood product transfusions during LT, but further investigation is needed. In particular, future studies should be tailored to establish if LT patients will likely benefit from four-factor PCC therapy.
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3-Factor versus 4-Factor Prothrombin Complex Concentrates for the Reversal of Vitamin K Antagonist-Associated Coagulopathy: A Systematic Review and Meta-analysis
Puchstein, D., Kork, F., Schöchl, H., Rayatdoost, F., Grottke, O.
Thrombosis and Haemostasis. 2023;123(1):40-53
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Abstract
Long-term anticoagulation is used worldwide to prevent or treat thrombotic events. Anticoagulant therapy using vitamin K antagonists (VKAs) is well established; however, anticoagulants carry an increased risk of potentially life-threatening bleeding. In cases of bleeding or need for surgery, patients require careful management, balancing the need for rapid anticoagulant reversal with risk of thromboembolic events. Prothrombin complex concentrates (PCCs) replenish clotting factors and reverse VKA-associated coagulopathy. Two forms of PCC, 3-factor (3F-PCC) and 4-factor (4F-PCC), are available. Using PRISMA methodology, we systematically reviewed whether 4F-PCC is superior to 3F-PCC for the reversal of VKA-associated coagulopathy. Of the 392 articles identified, 48 full texts were reviewed, with 11 articles identified using criteria based on the PICOS format. Data were captured from 1,155 patients: 3F-PCC, n = 651; 4F-PCC, n = 504. ROBINS-I was used to assess bias. Nine studies showed international normalized ratio (INR) normalization to a predefined goal, ranging from ≤1.5 to ≤1.3, following PCC treatment. Meta-analysis of the data showed that 4F-PCC was favorable compared with 3F-PCC overall (odds ratio [OR]: 3.50; 95% confidence interval [CI]: 1.88-6.52, p < 0.0001) and for patients with a goal INR of ≤1.5 or ≤1.3 (OR: 3.45; 95% CI: 1.42-8.39, p = 0.006; OR: 3.25; 95% CI: 1.30-8.13, p = 0.01, respectively). However, heterogeneity was substantial (I (2) = 62%, I (2) = 70%, I (2) = 64%). Neither a significant difference in mortality (OR: 0.72; 95% CI: 0.42-1.24, p = 0.23) nor in thromboembolisms was reported. These data suggest that 4F-PCC is better suited than 3F-PCC for the treatment of patients with VKA-associated coagulopathy, but further work is required for a definitive recommendation.
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Prothrombin complex concentrate (PCC) for treatment of trauma-induced coagulopathy: systematic review and meta-analyses
Hannadjas, I., James, A., Davenport, R., Lindsay, C., Brohi, K., Cole, E.
Critical care (London, England). 2023;27(1):422
Abstract
BACKGROUND Trauma-induced coagulopathy (TIC) is common in trauma patients with major hemorrhage. Prothrombin complex concentrate (PCC) is used as a potential treatment for the correction of TIC, but the efficacy, timing, and evidence to support its use in injured patients with hemorrhage are unclear. METHODS A systematic search of published studies was performed on MEDLINE and EMBASE databases using standardized search equations. Ongoing studies were identified using clinicaltrials.gov. Studies investigating the use of PCC to treat TIC (on its own or in combination with other treatments) in adult major trauma patients were included. Studies involving pediatric patients, studies of only traumatic brain injury (TBI), and studies involving only anticoagulated patients were excluded. Primary outcomes were in-hospital mortality and venous thromboembolism (VTE). Pooled effects of PCC use were reported using random-effects model meta-analyses. Risk of bias was assessed for each study, and we used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence. RESULTS After removing duplicates, 1745 reports were screened and nine observational studies and one randomized controlled trial (RCT) were included, with a total of 1150 patients receiving PCC. Most studies used 4-factor-PCC with a dose of 20-30U/Kg. Among observational studies, co-interventions included whole blood (n = 1), fibrinogen concentrate (n = 2), or fresh frozen plasma (n = 4). Outcomes were inconsistently reported across studies with wide variation in both measurements and time points. The eight observational studies included reported mortality with a pooled odds ratio of 0.97 [95% CI 0.56-1.69], and five reported deep venous thrombosis (DVT) with a pooled OR of 0.83 [95% CI 0.44-1.57]. When pooling the observational studies and the RCT, the OR for mortality and DVT was 0.94 [95% CI 0.60-1.45] and 1.00 [95% CI 0.64-1.55] respectively. CONCLUSIONS Among published studies of TIC, PCCs did not significantly reduce mortality, nor did they increase the risk of VTE. However, the potential thrombotic risk remains a concern that should be addressed in future studies. Several RCTs are currently ongoing to further explore the efficacy and safety of PCC.
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Four-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-associated bleeding: a meta-analysis of fixed versus variable dosing
Chiasakul T, Crowther M, Cuker A
Research and practice in thrombosis and haemostasis. 2023;7(2):100107
Abstract
BACKGROUND The optimal dosing strategy of four-factor prothrombin complex concentrate (4F-PCC) to treat oral factor Xa (FXa) inhibitor-associated bleeding has not been established. OBJECTIVES To evaluate the effectiveness and safety of fixed versus variable 4F-PCC dosing for the management of FXa inhibitor-associated bleeding. METHODS A systematic literature search and meta-analysis of clinical studies was performed using PubMed, Embase, and Cochrane databases from inception to January 2022. The primary outcomes included hemostatic effectiveness, mortality, and thromboembolic events. Secondary outcomes included 4F-PCC usage, total length of stay in hospital and in intensive care units, and time to 4F-PCC administration. The pooled incidence or mean was calculated using a random-effects model and compared between the 2 dosing strategies. RESULTS Twenty-five studies were included and data from 1,760 patients (fixed dosing, n = 228; variable dosing, n = 1,532) were analyzed. There were no significant differences in hemostatic effectiveness, thromboembolic events, or mortality rates between the dosing strategies. Hospital length of stay was significantly longer in the fixed-dosing group, with a mean stay of 7.4 days (95% CI: 3.6-11.1) compared to 5.9 days (95% CI: 5.5-6.3) in the variable-dosing group (P < 0.001). The mean initial 4F-PCC dose was significantly higher with variable dosing than fixed dosing (38 IU/kg; 95% CI: 32-44 vs. 27 IU/kg; 95% CI: 26-28, P < 0.001). CONCLUSIONS A fixed-dosing strategy appears to be a safe and effective alternative to variable weight-based dosing and was associated with lower 4F-PCC usage. However, direct comparative studies are needed to confirm these results.
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Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial
Bouzat P, Charbit J, Abback PS, Huet-Garrigue D, Delhaye N, Leone M, Marcotte G, David JS, Levrat A, Asehnoune K, et al
Jama. 2023
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Editor's Choice
Abstract
IMPORTANCE Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption. OBJECTIVE To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021. INTERVENTIONS Intravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines. MAIN OUTCOMES AND MEASURES The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety). RESULTS Of 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03). CONCLUSIONS AND RELEVANCE Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03218722.
PICO Summary
Population
Patients with trauma at risk of massive transfusion enrolled in the PROCOAG trial, in 12 level I trauma centers in France (n= 327).
Intervention
Intravenous administration of 4-factor prothrombin complex concentrate (4F-PCC group, n= 164).
Comparison
Saline solution (placebo group, n= 160).
Outcome
The primary outcome was the total number of all blood product units (RBC, FFP, and platelet concentrate) consumed within the first 24 hours after arrival in the trauma bay. The secondary outcomes were arterial or venous thromboembolic events. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs. 11 [6-19] U in the placebo group; absolute difference, 0.2 U, 95% CI [-2.99, 3.33]). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs. 37 patients (24%) in the placebo group (absolute difference, 11%, 95% CI [1%, 21%]; relative risk, 1.48, 95% CI [1.04, 2.10]).
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Prothrombin Complex Concentrate vs Plasma for Post-Cardiopulmonary Bypass Coagulopathy and Bleeding: A Randomized Clinical Trial
Smith MM, Schroeder DR, Nelson JA, Mauermann WJ, Welsby IJ, Pochettino A, Montonye BL, Assawakawintip C, Nuttall GA
JAMA surgery. 2022
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Editor's Choice
Abstract
IMPORTANCE Post-cardiopulmonary bypass (CPB) coagulopathy and bleeding are among the most common reasons for blood product transfusion in surgical practices. Current retrospective data suggest lower transfusion rates and blood loss in patients receiving prothrombin complex concentrate (PCC) compared with plasma after cardiac surgery. OBJECTIVE To analyze perioperative bleeding and transfusion outcomes in patients undergoing cardiac surgery who develop microvascular bleeding and receive treatment with either PCC or plasma. DESIGN, SETTING, AND PARTICIPANTS A single-institution, prospective, randomized clinical trial performed at a high-volume cardiac surgical center. Patients were aged 18 years or older and undergoing cardiac surgery with CPB. Patients undergoing complex cardiac surgical procedures (eg, aortic replacement surgery, multiple procedures, or repeated sternotomy) were preferentially targeted for enrollment. During the study period, 756 patients were approached for enrollment, and 553 patients were randomized. Of the 553 randomized patients, 100 patients met criteria for study intervention. INTERVENTIONS Patients with excessive microvascular bleeding, a prothombin time (PT) greater than 16.6 seconds, and an international normalized ratio (INR) greater than 1.6 were randomized to receive treatment with either PCC or plasma. The PCC dose was 15 IU/kg or closest standardized dose; the plasma dose was a suggested volume of 10 to 15 mL/kg rounded to the nearest unit. MAIN OUTCOMES AND MEASURES The primary outcome was postoperative bleeding (chest tube output) from the initial postsurgical intensive care unit admission through midnight on postoperative day 1. Secondary outcomes were PT/INR, rates of intraoperative red blood cell (RBC) transfusion after treatment, avoidance of allogeneic transfusion from the intraoperative period to the end of postoperative day 1, postoperative bleeding, and adverse events. RESULTS One hundred patients (mean [SD] age, 66.8 [13.7] years; 61 [61.0%] male; and 1 [1.0%] Black, 1 [1.0%] Hispanic, and 98 [98.0%] White) received the study intervention (49 plasma and 51 PCC). There was no significant difference in chest tube output between the plasma and PCC groups (median [IQR], 1022 [799-1575] mL vs 937 [708-1443] mL). After treatment, patients in the PCC arm had a greater improvement in PT (effect estimate, -1.37 seconds [95% CI, -1.91 to -0.84]; P < .001) and INR (effect estimate, -0.12 [95% CI, -0.16 to -0.07]; P < .001). Fewer patients in the PCC group required intraoperative RBC transfusion after treatment (7 of 51 patients [13.7%] vs 15 of 49 patients [30.6%]; P = .04); total intraoperative transfusion rates were not significantly different between groups. Seven (13.7%) of 51 patients receiving PCCs avoided allogeneic transfusion from the intraoperative period to the end of postoperative day 1 vs none of those receiving plasma. There were no significant differences in postoperative bleeding, transfusions, or adverse events. CONCLUSIONS AND RELEVANCE The results of this study suggest a similar overall safety and efficacy profile for PCCs compared with plasma in this clinical context, with fewer posttreatment intraoperative RBC transfusions, improved PT/INR correction, and higher likelihood of allogeneic transfusion avoidance in patients receiving PCCs. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02557672.
PICO Summary
Population
Patients undergoing cardiac surgery who developed microvascular bleeding (n= 100).
Intervention
Prothrombin complex concentrate (PCC), (n= 51).
Comparison
Plasma (n= 49).
Outcome
The primary outcome was postoperative bleeding (chest tube output) from the initial postsurgical intensive care unit admission through midnight on postoperative day 1. There was no significant difference in chest tube output between the plasma and PCC groups (median [IQR], 1022 [799, 1575] mL vs. 937 [708, 1443] mL). After treatment, patients in the PCC group had a greater improvement in prothombin time, (effect estimate, -1.37 seconds, 95% CI [-1.91, -0.84]) and international normalized ratio (effect estimate, -0.12, 95% CI [-0.16, -0.07]). Fewer patients in the PCC group required intraoperative red blood cell transfusion after treatment (7 of 51 patients [13.7%] vs. 15 of 49 patients [30.6%]); total intraoperative transfusion rates were not significantly different between groups. Seven (13.7%) of 51 patients receiving PCCs avoided allogeneic transfusion from the intraoperative period to the end of postoperative day 1 vs. none of those receiving plasma. There were no significant differences in postoperative bleeding, transfusions, or adverse events.
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The use of FEIBA for refractory bleeding in cardiac surgery - a systematic review
Khoury W, Servito M, Wang L, Baranchuk A, Callum J, Payne D, El-Diasty M
Expert Review of Cardiovascular Therapy. 2022
Abstract
INTRODUCTION Significant blood loss during cardiac surgery is associated with a significant increase in morbidity and mortality. Factor Eight Inhibitor Bypassing Activity (FEIBA), a hemostatic bypassing agent mainly used in hemophiliac patients, has also been used for intractable surgical bleeding during cardiac surgical procedures in non-hemophiliac patients. However, concerns exist that its use may be linked to increased incidence of perioperative adverse effects including thrombotic complications. AREAS COVERED A systematic literature search was performed on MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases for all studies that reported the administration of FEIBA for treatment of bleeding during adult cardiac surgery in non-hemophiliac patients. After selecting of title and abstracts, two authors assessed the methodological quality of the full-text articles prior to final inclusion in the manuscript. EXPERT OPINION The safety profile of FEIBA was determined through an aggregate count of adverse events. Major complications included renal failure, re-operation for unresolved bleeding, postoperative mortality, and thromboembolic events. Overall, there is insufficient robust evidence to make a definitive conclusion about the safety or efficacy of using of FEIBA as a hemostatic agent in the setting of cardiac surgery.