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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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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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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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Prophylactic fresh frozen plasma versus prothrombin complex concentrate for preprocedural management of the coagulopathy of liver disease: A systematic review
Evans CR, Cuker A, Crowther M, Pishko AM
Research and practice in thrombosis and haemostasis. 2022;6(4):e12724
Abstract
BACKGROUND The optimal prophylactic preprocedural management of patients with coagulopathy due to liver disease is not known. OBJECTIVES Our objective was to compare the efficacy and safety of fresh frozen plasma (FFP) with prothrombin complex concentrate (PCC) in the preprocedural management of patients with coagulopathy of liver disease. METHODS We conducted a systematic review to examine published evidence regarding treatment with FFP or PCC in adults with coagulopathy of liver disease undergoing an invasive procedure. Direct comparisons and single-arm studies were eligible. Efficacy outcomes included major bleeding, mortality, and correction of prothrombin time (PT) and/or international normalized ratio (INR). Safety outcomes included thrombosis and transfusion-related complications. RESULTS A total of 95 articles were identified for full-text review. Nine studies were eligible and included in the review. No randomized trials comparing FFP versus PCC were identified. Only two studies directly compared FFP versus PCC. In these studies, PCC appeared to result in higher rates of correction of PT/INR, but bleeding outcomes were not different. In the single-arm studies, bleeding events appeared low overall. Volume overload was the most common recorded adverse event in patients receiving FFP. Thromboembolic events occurred rarely, but exclusively in the PCC group. Due to heterogeneity in study definitions and bias, meta-analysis was not possible. Our study found no evidence to favor a specific product over another. CONCLUSIONS Insufficient data exist on the effects of FFP versus PCC administration before invasive procedures in patients with coagulopathy of liver disease to make conclusions with respect to relative efficacy or safety.
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Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage: A Systematic Review and Meta-analysis
Chaudhary R, Singh A, Chaudhary R, Bashline M, Houghton DE, Rabinstein A, Adamski J, Arndt R, Ou NN, Rudis MI, et al
JAMA network open. 2022;5(11):e2240145
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Editor's Choice
Abstract
IMPORTANCE Direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited. OBJECTIVE To evaluate the safety and outcomes of DOAC reversal agents among patients with ICH. DATA SOURCES PubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022. STUDY SELECTION The eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded. DATA EXTRACTION AND SYNTHESIS Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model. MAIN OUTCOMES AND MEASURES The primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent. RESULTS A total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events. CONCLUSIONS AND RELEVANCE In the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.
PICO Summary
Population
Adult patients with intracranial hemorrhage receiving treatment with a direct oral anticoagulant (36 studies, n= 1,832).
Intervention
4-factor prothrombin complex concentrate (4F-PCC), (n= 967).
Comparison
Andexanet alfa (AA), (n= 525). Idarucizumab(n= 340).
Outcome
For 4F-PCC, anticoagulation reversal was 77% (95% CI 72% to 82%; I2 = 55%); all-cause mortality, 26% (95% CI 20% to 32%; I2 = 68%), and thromboembolic events, 8% (95% CI 5% to 12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI 67% to 81%; I2 = 48%); all-cause mortality, 24% (95% CI 16% to 34%; I2 = 73%), and thromboembolic events, 14% (95% CI 10% to 19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI 55% to 95%; I2 = 41%), all-cause mortality, 11% (95% CI 8% to 15%, I2 = 0%), and thromboembolic events, 5% (95% CI 3% to 8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events.
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Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants
Gómez-Outes, A., Alcubilla, P., Calvo-Rojas, G., Terleira-Fernández, A. I., Suárez-Gea, M. L., Lecumberri, R., Vargas-Castrillón, E.
Journal of the American College of Cardiology. 2021;77(24):2987-3001
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Editor's Choice
Abstract
BACKGROUND Direct oral anticoagulants (DOACs) have shown a positive benefit-risk balance in both clinical trials and real-world data, but approximately 2% to 3.5% of patients experience major bleeding annually. Many of these patients require hospitalization, and the administration of reversal agents may be required to control bleeding. OBJECTIVES The aim of this study was to investigate clinical outcomes associated with the use of 4-factor prothrombin complex concentrates, idarucizumab, or andexanet for reversal of severe DOAC-associated bleeding. METHODS The investigators systematically searched for studies of reversal agents for the treatment of severe bleeding associated with DOAC. Mortality rates, thromboembolic events, and hemostatic efficacy were meta-analyzed using a random effects model. RESULTS The investigators evaluated 60 studies in 4,735 patients with severe DOAC-related bleeding who were treated with 4-factor prothrombin complex concentrates (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936). The mortality rate was 17.7% (95% confidence interval [CI]: 15.1% to 20.4%), and it was higher in patients with intracranial bleedings (20.2%) than in patients with extracranial hemorrhages (15.4%). The thromboembolism rate was 4.6% (95% CI: 3.3% to 6.0%), being particularly high with andexanet (10.7%; 95% CI: 6.5% to 15.7%). The effective hemostasis rate was 78.5% (95% CI: 75.1% to 81.8%) and was similar regardless of the reversal agent considered. The rebleeding rate was 13.2% (95% CI: 5.5% to 23.1%) and 78% of rebleeds occurred after resumption of anticoagulation. The risk of death was markedly and significantly associated with failure to achieve effective hemostasis (relative risk: 3.63; 95% CI: 2.56 to 5.16). The results were robust regardless of the type of study or the hemostatic scale used. CONCLUSIONS The risk of death after severe DOAC-related bleeding remains significant despite a high rate of effective hemostasis with reversal agents. Failure to achieve effective hemostasis strongly correlated with a fatal outcome. Thromboembolism rates are particularly high with andexanet. Comparative clinical trials are needed.
PICO Summary
Population
Patients with severe direct oral anticoagulant-related bleeding (60 studies, n= 4,735).
Intervention
4-factor prothrombin complex concentrates (n= 2,688).
Comparison
Idarucizumab (n= 1,111), or andexanet (n= 936).
Outcome
Mortality rates, thromboembolic events, and haemostatic efficacy were meta-analyzed using a random effects model. The mortality rate was 17.7%; 95% CI [15.1%, 20.4%], and it was higher in patients with intracranial bleedings (20.2%) than in patients with extracranial haemorrhages (15.4%). The thromboembolism rate was 4.6%; 95% CI [3.3%, 6.0%], being particularly high with andexanet (10.7%; 95% CI [6.5%, 15.7%]). The effective haemostasis rate was 78.5%; 95% CI [75.1%, 81.8%] and was similar regardless of the reversal agent considered. The rebleeding rate was 13.2%; 95% CI [5.5%, 23.1%] and 78% of rebleeds occurred after resumption of anticoagulation. The risk of death was markedly and significantly associated with failure to achieve effective haemostasis (relative risk: 3.63; 95% CI [2.56, 5.16]). The results were robust regardless of the type of study or the haemostatic scale used.
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Quality evaluation of case series describing four-factor prothrombin complex concentrate in oral factor Xa inhibitor-associated bleeding: a systematic review
Costa, O. S., Baker, W. L., Roman-Morillo, Y., McNeil-Posey, K., Lovelace, B., White, C. M., Coleman, C. I.
BMJ open. 2020;10(11):e040499
Abstract
INTRODUCTION As oral factor Xa (oFXa) inhibitor use has increased, so has publication of case series describing related bleeding managed with four-factor prothrombin complex concentrate (4F-PCC). OBJECTIVE This review aimed to identify case series describing 4F-PCC management of oFXa inhibitor-related bleeding and appraise their methodological and reporting quality. DESIGN We searched Medline and EMBASE (1 January 2011 to 31 May 2020) to identify series of ≥10 patients with oFXa inhibitor-related major bleeding given off-label 4F-PCC. Case series were evaluated using a validated tool adapted for this topic. The tool addressed patient selection, bleed/outcome ascertainment, causal/temporal association and reporting. RESULTS We identified 14 case series. None had ≥100 patients (range=13-84), three were prospective, two detailed appropriate inclusion criteria and four noted consecutive inclusion. While 12 series provided clear/appropriate methods for diagnosis of intracranial haemorrhage (ICH); none did so for extracranial bleeds and it was not clear whether bleeding was adjudicated in any. Haemostatic effectiveness, thrombosis and mortality were together evaluated in 12 series, but only seven used validated methods to evaluate/diagnosis haemostasis in ICH, six in gastrointestinal bleeds, five in other bleeds and three in thrombosis. Independent adjudication of haemostasis (n=1) and thrombosis (n=2) was infrequent. Thirty-day follow-up for mortality and thrombosis was noted in five and seven series. Anticoagulation measurement/levels in at least some patients were conveyed in three series. Few series provided data on anticoagulant agent/dose (n=4), time from anticoagulant (n=4), time-to-reversal (n=7), baseline (n=7) or change (n=0) in neurologic function. CONCLUSIONS Although many case series describe off-label use of 4F-PCC for oFXa inhibitor-related bleeding, methodological flaws and/or poor reporting necessitates caution in interpretation.
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Efficacy and safety of prothrombin complex concentrate for vitamin K antagonist-associated intracranial hemorrhage: a systematic review and meta-analysis
Pan R, Cheng J, Lai K, Huang Q, Wu H, Tang Y
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2019
Abstract
BACKGROUND Prothrombin complex concentrate (PCC) is the treatment of choice in vitamin K antagonist-associated intracranial hemorrhage (VKA-ICH). However, the efficiency and safety associated with their use remain unclear. AIMS This study aimed to assess the current evidence of the clinical outcomes in patients with VKA-ICH treated with or without PCC. A meta-analysis was conducted. Two randomized controlled trials and 19 observational studies were included. PCC use demonstrated a significant increased likelihood of international normalized ratio (INR) normalization (OR = 3.76; 95% CI 1.74-8.12), shortened time to INR correction (MD = - 1.30; 95% CI - 2.08 to - 0.53) and reduction of hematoma expansion (HE) rate (OR = 0.37; 95% CI 0.23-0.60). Although PCC use revealed a statistical reduction at 30-day mortality (OR = 0.62; 95% CI 0.50-0.78), the result was inconsistent with mortality at discharge (OR = 1.03; 95% CI 0.68-1.57) and 90-day follow-up (OR = 0.50; 95% CI 0.24-1.07), both of which yielded no significant difference. When subgroup analyses were performed focus on PCC only treatment with FFP, no statistically significant difference was observed in 30-day mortality (OR = 0.43; 95% CI 0.11-1.71) as well. Besides, significant difference was not found in neurologic improvement at discharge (OR = 1.85; 95% CI 0.32-10.75), 30-day follow-up (OR = 3.00; 95% CI 0.93-9.70), or 90-day follow-up (OR = 1.55; 95% CI 0.84-2.86). No statistically significant difference was noted in the risk of thromboembolism following PCC administration (OR = 0.61; 95% CI 0.23-1.63). CONCLUSIONS PCC use for VKA-ICH reversal was associated with a significant reduction in INR and HE rate, without an increased risk of thromboembolic events. However, this reduction was not associated with improvement in neurologic deficits or overall survival. Well-designed randomized trials with special considerations to the aspect are necessary.
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Systematic review: 3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal: Does it matter?
Voils SA, Baird B
Thrombosis Research. 2012;130((6):):833-40.
Abstract
INTRODUCTION Prothrombin complex concentrates are used for rapid reversal of vitamin K antagonists in patients with bleeding or those requiring surgery or invasive procedures. Current guidelines suggest 4-factor products are preferred over 3-factor prothrombin complex concentrates. MATERIALS AND METHODS We performed a systematic review comparing the effectiveness of 3-factor to 4-factor prothrombin complex concentrates in normalizing the international normalized ratio to <=1.5 in patients with acquired coagulopathy due to vitamin K antagonist use. Studies reporting administration of prothrombin complex concentrates for emergent reversal of vitamin K antagonists that included results of baseline prothrombin time/international normalized ratio and follow-up testing within 60minutes of prothrombin complex concentrates administration were included. RESULTS A total of 18 studies were included representing 654 patients. The most common indications for prothrombin complex concentrate were intracerebral hemorrhage, urgent surgery or invasive procedure, and gastrointestinal bleeding. Baseline international normalized ratio values ranged from 3.3-5.1 in the 3-factor group and from 2.3 to greater than 20 in the 4-factor group. The international normalized ratio repeated within one hour of prothrombin complex concentrates administration ranged from 1.2-1.9 in the 3-factor group and 1.0-1.9 in the 4-factor group. International normalized ratio decreased to <=1.5 within one hour after prothrombin complex concentrates administration in 6 of 9 studies in the 3-factor group, and 12 of 13 studies in the 4-factor group. CONCLUSION More reliable correction of the international normalized ratio was seen with 4-factor compared to 3-factor prothrombin complex concentrates which may have clinical implications since 4-factor products are unavailable in some countries. Copyright Copyright 2012 Elsevier Ltd. All rights reserved.