Efficacy and safety of activated prothrombin complex concentrate for the reversal of vitamin K antagonist major bleeding

Data on the use of activated prothrombin complex concentrate (aPCC) for the management of warfarin associated major bleeding is sparse. The objective of the study was to assess the achievement of effective clinical hemostasis using aPCC in patients presenting with major bleeding while on warfarin. We also assessed the safety of the drug. This retrospective study was conducted at a tertiary care teaching center in the USA where patients with major bleeding while receiving warfarin, and received aPCC were included. Efficacy of aPCC in achieving effective hemostasis was assessed according to the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. Efficacy was also assessed by achieving INR < 1.5 after treatment. The primary safety endpoint was the occurrence of any thromboembolic complications. A total of 67 patients were included in the study. The most common site for bleeding was intracerebral hemorrhage (n = 37, 55.2%), followed by gastrointestinal bleed (n = 26, 38.8%). Clinical hemostasis was achieved in 46 (68.7%) patients and of the 21 (31.3%) patients who did not achieve clinical hemostasis, 16 died. Thirty nine (58.2%) patients achieved INR < 1.5. Five (7.5%) patients developed thromboembolic complications. This study suggests that the use of aPCCs is effective in achieving effective hemostasis in patients on warfarin presenting with major bleeding.

www.nature.com/scientificreports/ Studies comparing 3PCC + rFVIIa with 4PCC found that 3PCC + rFVIIa achieved greater reductions in International Normalization Ratio (INR) compared to 4PCC, although both regimens were able to achieve an INR < 1.5. Additionally, these studies found that 3PCC + FVIIa had tenfold higher incidence of deep venous thrombosis (DVT) compared to 4PCC 4 . Extrapolations from these findings, along with previous hemophiliarelated data, have led to concerns that aPCC therapy carries inherently increased risks for coagulopathies. However, lower doses of aPCC have been evaluated for the treatment of emergent, VKA-related bleeding. Researchers found no difference in the ability or time to achieve a post-treatment INR < 1.5. Furthermore, they found no difference in post-treatment thrombotic complications when comparing aPCC and 4PCC 5 .
Since data on the use of aPCC for VKA associated major bleeding is sparse, we conducted this study to assess the efficacy and safety of aPCC in patients presenting with major bleeding while on the VKA, warfarin.

Methods
This is a single center, retrospective analysis conducted between January 2019 and December 2020 at a tertiary care teaching center, Huntsville Hospital, Alabama, USA. Patients were eligible for inclusion if they were ≥ 18 years of age and presented with major bleeding while receiving warfarin, and received the aPCC, FEIBA (Anti-Inhibitor Coagulant Complex, Takeda). Patients with INR elevations contributable to other causes, such as chronic cirrhosis, acute hepatotoxicity, or shock liver, were excluded. As per hospital protocol, FEIBA was given intravenously at a dose of 500 units if the INR was < 5, and 1000 units if INR ≥ 5. In addition, all patients received intravenous vitamin K at a dose of 10 mg (Supplementary Information).
Major bleeding was defined according to International Society of Thrombosis and Hemostasis (ISTH) definition for major bleeding in nonsurgical patients as (1) fatal bleeding, (2) symptomatic bleeding in a critical area or organ, (3) bleeding causing a fall in hemoglobin level of ≥ 2 g/dL, or leading to transfusion of ≥ 2 units of whole blood or red cells 6 . The efficacy of aPCC in achieving effective hemostasis was assessed according to ISTH Scientific and Standardization Subcommittee criteria 7 . The efficacy was also assessed by achieving INR < 1.5 after administration of aPCC. Baseline INR was obtained for each patient prior to aPCC administration with follow-up INRs at 30 min and one hour after administration. The primary safety endpoint was the occurrence of any thromboembolic complication after treatment with aPCC including myocardial infarction, stroke, transient ischemic attack, DVT, and pulmonary embolism (PE).
Data were collected from the medical records of patients, including demographic information, physicians' orders and notes, laboratory values, and any other relevant details. Patients were followed until discharge or death. Waiver of informed consent and ethical approval for this study was obtained from Huntsville Hospital's Institutional Review Committee and all methods were performed in accordance with the relevant guidelines and regulations. Data were analyzed with descriptive statistics and frequency distributions.
Statistical analyses were conducted with SAS (version 9.4, SAS Institute Inc, Cary, NC). Normality was assessed for continuous variables by the Shapiro-Wilk test, and the Kolmogorov-Smirnov test. All continuous data was found to be non-Gaussian; thus, the Mann Whitney U test was used to assess statistical differences between groups. All categorical variables were evaluated using Chi Squared and Fisher's Exact as appropriate.
Ethics approval and consent to participate. Ethical approval for this study was obtained from Huntsville Hospital's Institutional Review Committee.

Results
A total of 67 patients met the inclusion criteria during the study period and were included, of which 41 were males (61.1%) and 26 (38.9%) were females. The mean age ± SD was 72.8 ± 10.6 years. The most common indication for warfarin use was AF (n = 32, 47.8%), followed by mechanical valve (n = 15, 22.4%), and DVT/PE (n = 12, 17.9%). The most common site for bleeding was intracerebral hemorrhage (ICH) (n = 37, 55.2%), followed by gastrointestinal (GI) bleed (n = 26, 38.8%). Table 1 Table 2 describes bleeding management outcomes, Table 3 describes INR values upon admission and after receiving aPCC, and Table 4 describes characteristics of patients who died.
In addition to aPCC, patients received additional management to control bleeding; 15 patients received FFP, and seven patients who were on anti-platelet therapy or had thrombocytopenia received platelet transfusions. After receiving aPCC, five patients (7.5%) developed thromboembolic complications (three of them received FFP in addition to aPCC); four patients developed DVT (one on day four of admission, two on day five, and one on day 20), and one patient developed PE on day 15 of admission.   Due to the high levels of coagulation factors contained in aPCC, the thrombotic complications associated with its use remain a concern. In this study, five patients (7.5%) developed thrombotic complications, three of whom received FFP along with aPCC, similar to the findings of a study involving 388 patients where 4PCC was used (7.3%) 9 . On the other hand, in a meta-analysis of 1032 patients where 4PCC was used to reverse the effect of VKA, the incidence of thromboembolic events was 1.8% 10 . The addition of FFP to aPCC could have significantly increased the risk of thromboembolic events in this study.
When analyzing obese patients, we found results similar to those in recent studies. McKinney, et al. reported significantly higher proportions of non-obese patients achieving INR values of 1.4 or less. However, these lower INR reversal rates were not associated with lower rates of hemostasis 11 .
Our study has several limitations. This was a single center retrospective chart review with a small sample and without a comparator group. Moreover, some patients received FFP and platelet transfusions which can influence the outcomes. In addition, the dose of aPCC used in the study is based on limited data and may not be the optimal dosing regimen. Furthermore, we were not able to follow patients after discharge from the hospital which may underrate the number of thrombotic events. Nevertheless, despite these limitations, this study adds novel and important information involving the use of aPCC for the reversal of warfarin.

Conclusion
This study suggests that the use of aPCC is effective in achieving effective hemostasis in patients on warfarin presenting with major bleeding and thrombotic complications associated with its use remain a concern. Further controlled studies are needed to confirm these findings and conclude the optimal dosing regimen for maximal efficacy and safety.