INTRODUCTION
Warfarin is a commonly prescribed anticoagulant medication for treating and preventing thromboembolic events that primarily operates by inhibiting the synthesis of vitamin K-dependent clotting factors. Despite the availability of safer agents, particularly direct oral anticoagulants, warfarin remains the preferred agent in several conditions due to its cost-effectiveness, well-established monitoring and dose-adjustment protocols, and reliable reversal options [1]. Major bleeding secondary to warfarin use is estimated to occur in 2% to 5% of patients annually, with fatal outcomes in up to 4% of patients [2]. The availability of rapid and effective reversal agents for warfarin-associated major bleeding is essential to control adverse consequences.
Vitamin K, often used in combination with other agents such as fresh frozen plasma (FFP) and prothrombin complex concentrates (PCCs), is widely utilized to reverse warfarin-associated bleeding [3–5]. However, this approach has since fallen out of favor due to the limitations of FFP, including increased risk of volume overload, longer preparation time, and the necessity for ABO blood group compatibility. Four-factor PCC (4-PCC), which contains both coagulation and anticoagulation factors (factors II, VII, IX, and X and proteins C and S), has been shown to be safe and effective against warfarin-associated bleeding. Several advantages of 4-PCCs are that they do not require ABO blood group compatibility, can be stored at room temperature, can be rapidly prepared and administered to the patient, and impose a less significant volume burden [6].
The American College of Cardiology guidelines recommend 4-PCC in addition to vitamin K for warfarin-induced bleeding. However, the optimal dose of 4-PCC remains unknown, with different guidelines addressing both weight-based dosing using the international normalized ratio (INR) and fixed dosing [7]. The manufacturer recommends a weight-based approach, which involves 25 to 50 units of 4-PCC per kilogram of body weight, based on the baseline INR. This results in dosing variability between patients, but it has been associated with a higher rate of achievement of the target INR [7]. Recent studies on fixed-dose administration, providing 500 to 2,000 units per patient, have shown results comparable to those obtained following the manufacturer's recommendations [8–12]. The goal of using a fixed dose of 4-PCC is to maintain efficacy while targeting a lower risk of thromboembolic complications, eliminating the need for complex dose calculations, and enabling faster administration. This approach also has the potential to reduce medication costs for patients and hospitals. Multiple studies have assessed the clinical outcomes of variable- versus fixed-dose strategies; however, the conclusions have been inconsistent. Therefore, an updated systematic review and meta-analysis of clinical studies is needed to evaluate whether a fixed dose of 4-PCC confers advantages over a variable-dose strategy in patients requiring warfarin reversal.
METHODS
Search strategy
The research team adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to conduct this systematic review. The review involved the PubMed, Embase, and Cochrane databases from their inception until October 2023, imposing no time or language restrictions [13,14].
Study selection
The primary investigator set the study objectives and outlined the selection criteria to the research team members. Eligibility criteria were defined using the PICO (population, intervention, comparator, and outcomes) framework. The search process utilized pre-identified headings and keywords, including the following: "blood coagulation factors” OR “4-factor prothrombin complex concentrate” OR “4-factor PCC, 4f-PCC, warfarin” OR “vitamin K antagonists” OR “Coumadin." Inclusion criteria were as follows: (1) adults ≥16 years of age; (2) randomized controlled trials or prospective or retrospective observational studies; (3) studies comparing 4-factor fixed-dose versus variable-dose PCC; and (4) studies evaluating at least one of the predetermined primary or secondary outcomes. Excluded were studies enrolling pediatric patients or using 4-PCC for bleeding prevention without disaggregated outcomes. The screening process involved two steps: initial screening of all titles and abstracts using pre-identified headings and keywords, followed by verification by a senior team member. After training, five reviewers assessed studies for inclusion, and references of included studies were manually searched.
Outcome measures
Five reviewers evaluated effectiveness and safety outcome measures, extracting data using a standardized form. Primary outcomes included hemostatic effectiveness as defined by the original authors, mortality, and thromboembolic events, encompassing both arterial (stroke, myocardial infarction, arterial thromboembolism) and venous (deep vein thrombosis, pulmonary embolism) events. Secondary outcomes measured the number of patients reaching the predetermined INR goal and those requiring additional 4-PCC therapy. Two subgroup analyses were conducted to compare results between patients achieving a goal INR <1.5 versus INR <2 and to examine the impact of 4-PCC dosing strategies on the type of bleeding (intracranial hemorrhage [ICH] and non-ICH).
Assessment of study quality and publication bias
Risk of bias for each study was assessed using the Cochrane risk-of-bias tool for randomized trials ver. 2 (RoB 2) [13]. The methodological quality of observational studies was evaluated by two reviewers using the Newcastle-Ottawa Scale (NOS), which awards up to nine stars for observational cohort studies: four for patient selection, two for cohort comparability, and three for outcome assessment and follow-up adequacy. Study quality was categorized based on stars received: low (0–3 stars), medium (4–6 stars), and high (7–9 stars). Three authors assessed study quality, with a fourth author consulted in cases of disagreement. Data collected were study authors, publication year, design, prothrombin concentration and dose used, adjunctive therapy, patient numbers in treatment and control groups, follow-up duration, and clinical outcomes of interest [15].
Data synthesis and statistical analysis
The Mantel-Haenszel random-effects model calculated risk ratios (RRs) and corresponding 95% confidence intervals (CIs) to estimate pooled treatment effects of fixed and variable doses of 4-PCC for emergent warfarin reversal. This model was chosen due to the variability in patient populations and clinical outcomes among the studies. Study heterogeneity was assessed using Cochrane Q test and the I2 statistic, with I2 values of <25% indicating low, 25% to 75% moderate, and >75% high heterogeneity. A Cochrane Q test P-value of <0.1 indicated significant heterogeneity. Publication bias was evaluated using funnel plots. All statistical analyses were conducted using Stata ver. 15.0 (StataCorp).
RESULTS
Study selection
The literature search yielded 1,920 potential studies from the database, and an additional 11 records were identified manually through references. Of these, 1,831 studies were excluded based on initial screening. The remaining 89 studies underwent further screening for eligibility. Many of these studies were excluded because they either did not compare the two dosages or utilized interventions other than 4-PCC. Fourteen studies met our inclusion criteria and were subsequently included in our analysis. A flowchart outlining the literature search and selection process for the studies is presented in Fig. 1.
Study characteristics and quality assessment
Fourteen studies met the eligibility criteria, and their characteristics are summarized in Table 1 [3,8,11,16–26]. Most of the studies were either retrospective (nine studies) [3,8,11,19–23,25,26] or prospective (five studies) [3,16–18,24] in nature. All eligible cohort studies demonstrated high quality, with mean NOS scores ranging from 7 to 8 (Tables 1, 2) [3,8,11,16–26]. Each study aimed to compare the efficacy of fixed-dose versus variable-dose 4-PCC for reversal of emergent warfarin bleeding, including ICH and non-ICH. For the meta-analysis, data from a total of 1,663 patients across 14 studies were analyzed [3,8,11,16–26]. Among these studies, five were observational prospective studies [3,16–18,24], and the remaining nine were observational retrospective studies [8,11,19–23,25,26]. Each observational study included a comparison with a control group.
Hemostatic effectiveness
Hemostatic effectiveness was reported in 14 studies [3,8,11,16–26], with the pooled rate evaluated from data on 1,663 patients (906 in the fixed-dose group and 1,053 in the variable-dose group). The studies employed various criteria to assess hemostatic effectiveness. The most used definitions were an INR target less than 1.5 for major bleeding and less than 2.0 for minor bleeding. For ICH, hemostatic effectiveness was assessed by computed tomography imaging methods, which evaluated hematoma expansion based on the percentage increase compared to the initial scan. The proportion of patients who achieved hemostatic effectiveness significantly differed between the fixed and variable dosing strategies (RR, 0.84; 95% CI, 0.80–0.89; P<0.001). Overall, the studies exhibited moderate to high heterogeneity (I2=58%). A forest plot analysis depicting these data is presented in Fig. 2 [3,8,11,16–26]. In the subgroup analysis of the type of reported bleeding (ICH vs. non-ICH), the mortality rate was not statistically different between the two treatment strategies (ICH: RR, 1.26 [95% CI, 0.70–2.25]; non-ICH: RR, 0.86 [95% CI, 0.63 to 1.17]) (Fig. 3) [3,11,17–23,25,26].
Thromboembolic events
Eleven studies reported thromboembolic events, and pooled thromboembolic event rates were evaluated in 1,177 patients (542 in the fixed-dose group and 635 in the variable-dose group). Similar thromboembolic event rates were observed between the two dosing strategies (fixed-dose group at 3% vs. variable-dose group at 2%; RR, 1.27; 95% CI, 0.65–2.45; P=0.469). Overall, no heterogeneity (I2=0%) was detected among the selected studies. In the subgroup analysis, based on the type of reported bleeding (ICH vs. non-ICH), the rate of thromboembolic events was not significantly different between the two groups. A forest plot analysis to illustrate these data is presented in Fig. 4 [3,11,17–19,21–24,26].
PCC administration
Thirteen studies reported the need for an additional dose of 4-PCC. Overall, a significantly larger proportion of patients in the fixed-dose group (169 of 651, 26%) required an additional dose of 4-PCC compared to the variable-dose group (176 of 777, 23%; RR, 1.18; 95% CI, 1.07–1.31; P=0.004). The necessity for additional doses of 4-PCC based on the type of bleeding (ICH vs. non-ICH) was not significantly different in the subgroup analysis categorized by reversal indication (P=0.063 and P=0.261, respectively). A forest plot analysis illustrating these data is presented in Fig. 5 [3,8,11,17–21,24,25].
DISCUSSION
The objective of this meta-analysis and systematic review was to compare fixed- and variable-dose 4-PCC strategies based on patient weight and baseline INR for those requiring reversal of vitamin K antagonist (VKA). Our study addressed the use of variable 4-PCC doses (both fixed and weight/INR-based variable dosing as per the package insert) for VKA reversal. Fourteen studies with 1,663 patients receiving 4-PCC in two dosing strategies—fixed and variable—were identified for reversing VKAs in cases of significant bleeding or urgent surgery. We observed a standardized method of 4-PCC administration. Patients in the fixed-dose group were more likely to receive either 1,500 or 2,000 units compared to the variable-dose group, which primarily followed the package insert recommendations. Studies suggest that outcomes among VKA-treated bleeding patients are similar for fixed- and variable-dose 4-PCC [8–12]. These trials show that VKA-associated bleeding can be managed with fixed-dose 4-PCC, yet variable-dose strategies remain in practice. We determined that both dosing strategies were effective and safe for patients requiring VKA reversal since mortality rates and thromboembolic event rates did not differ statistically between the fixed and variable doses of 4-PCC. Efficacy and safety outcomes were consistent across subgroup analyses based on the indication and type of bleeding. While a target INR less than 1.5 was more frequently achieved in the variable-dosing group, routine implementation of a weight-based dosing strategy in emergency departments is not justified and could delay 4-PCC administration. These findings indirectly support guidelines recommending either fixed or variable doses as initial therapy for VKA reversal [7]. However, patients in the fixed-dose group were less likely to achieve the target INR <1.5 compared to those receiving variable doses and were more likely to require an additional 4-PCC dose. Variable versus fixed dosing strategies of 4-PCC for warfarin reversal have been extensively investigated, with studies highlighting the potential superiority of variable dosing in achieving target INR levels [16–22]. Despite this, other outcomes like mortality rates and thrombotic events, as well as the need for additional doses of 4-PCC, remained similar between the dosing groups [3,8,11,23–25]. A secondary aim of our study was to assess if any treatment strategies were associated with thromboembolic events. Eleven studies investigated these events following 4-PCC administration for major bleeding, with none finding an association between the type of 4-PCC administered and thromboembolic rates [8,11,17–23,25]. These outcomes were consistent irrespective of the type of bleeding reported. Additional research is warranted due to inconsistencies in follow-up rates between treatment groups. Finally, while most patients reportedly received a single dose of 4-PCC, repeated dosing was noted in some studies [3,11,17–19,21–24]. More patients in the fixed-dosage group received an additional 4-PCC dose, though this difference was not significant when considering the type of bleeding reported. In conclusion, our results corroborate prior systematic reviews, suggesting that initial treatment with fixed-dose 4-PCC may be beneficial over variable-dose treatment in the emergency department for VKA-related major bleeding. Multivariate analyses confirmed similar outcomes between the two treatment strategies. Given that almost all patients received 4-PCC in the emergency department, it remains unclear if alternative treatments (FFP and vitamin K) would influence practice or offer additional benefits.
Strengths and limitations
This meta-analysis and systematic review represents the most recent comprehensive assessment of 4-PCC administration in patients with VKA-related bleeding. It covers a diverse range of studies, including those involving urgent surgery, ICH, and non-ICH cases. Our approach aimed to provide a practical evaluation of fixed-dose versus variable-dose 4-PCC use, considering the various types of bleeding and their clinical implications. While acknowledging the strengths of the study, we also recognize several limitations. Most of the included studies were either retrospective or prospective, which could potentially influence the robustness of our findings. Variations in reporting and the emergent nature of interventions limited our ability to evaluate differences in diagnostic workup or alternative diagnoses among the studies. We refrained from assessing the correlation between post-administration changes in INR due to inconsistent reporting across the included studies. Additionally, important factors such as concurrent medication use and medical history, which could influence initial therapy decisions in the emergency department, were not uniformly considered. The study was unable to control for publication bias or ensure complete homogeneity across the included studies, which might have affected the overall analysis. In summary, while our study offers valuable insights into the comparative effectiveness of different 4-PCC dosing strategies, these findings are constrained by the limitations inherent in the diverse nature and reporting standards of the included studies. Further research that considers these limitations is essential to gain a more comprehensive understanding of optimal 4-PCC dosing in VKA-related bleeding scenarios.
Conclusions
This systematic review and meta-analysis showed that variable dosing of 4-PCC more successfully achieves the target INR for warfarin reversal compared to fixed dosing. However, the two dosing strategies have similar mortality and thromboembolic rates. While fixed dosing offers a simpler approach, it may require additional administration. Future studies should focus on optimizing dosing strategies to balance efficacy, safety, and practicality in various clinical scenarios. These findings suggest that these two dosing strategies can be considered viable options in clinical practice and should be distinguished depending on the specific clinical scenario.
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