To the Editor,
The publication by Daniele Orsc et al. [1] in Critical Care, titled "Andexanet alpha versus four-factor prothrombin complex concentrate in DOACs anticoagulation reversal: an updated systematic review and meta-analysis," has significant clinical implications. This present study obtained two key findings that may complement their conclusions.
The primary outcome of this meta-analysis revealed a higher thromboembolic event risk associated with Andexanet alpha when analyzing controlled (RCT and PSM) studies. However, the authors did not perform trial sequential analysis (TSA), potentially leading to type I and type II errors and premature conclusions. To address this, TSA Viewer version 0.9.5.10 Beta was utilized to determine if published studies provided sufficient evidence for reliable conclusions. The two-sided type I error was set at 5%, and 80% power was selected to calculate the required information size (RIS). The control group incidence was determined through meta-analysis. Results from the TSA showed that the blue Z-curve crossed the conventional boundary but not the TSA boundary (Fig. 1). Moreover, the data failed to meet the required information size (RIS = 1717). Consequently, conventional meta-analysis may yield false-positive results. Additional trials are necessary to confirm the difference in thromboembolic events between the groups.
Fig. 1.
Trial sequential analysis (TSA) for the rate of thromboembolic events. Blue Z curve stands for Z-values accumulated from the meta-analysis (combined relative risk). Pink dotted lines are indicative of conventional boundaries, whereas red solid lines stand for TSA boundaries. RIS, required information size
In the analysis of all-cause short-term mortality in retrospective studies, the authors included the studies with varying follow-up periods, ranging from 7-day, 28-day, 30-day, and in-hospital mortality. This variability may introduce inaccuracies in meta-analysis results due to factors such as persistent treatment effects and disease deterioration, potentially leading to heterogeneity and compromising result interpretation and conclusion reliability. To address this, a subgroup analysis using Revman5.3 software was conducted on six studies [2–7] that reported 30-day mortality. Employing a fixed-effects model, the risk ratio (RR) for the Andexanet alpha group was 0.62 (95% CI 0.47–0.84) compared to four-factor prothrombin complex in retrospective studies, as shown in Fig. 2. This difference achieved statistical significance. The discrepancies between these findings and those of the original meta-analysis highlight the importance of considering distinct time points when evaluating mortality rates in critically ill patients. Therefore, additional high-quality RCTs are necessary for validation purposes.
Fig. 2.
Forest plots for 30-day mortality in the retrospective studies
Author contributions
Tengfei Yang and Bo Zhao conceptualized the study, performed the literature research, and drafted the manuscript. Bo Zhao supervised the research, provided critical revisions, and contributed to the final manuscript. Both authors read and approved the final version of the manuscript for submission.
Funding
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Competing interests
None.
Footnotes
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References
- 1.Orso D, Fonda F, Brussa A, Comisso I, Auci E, Sartori M, et al. Andexanet alpha versus four-factor prothrombin complex concentrate in DOACs anticoagulation reversal: an updated systematic review and meta-analysis. Crit Care. 2024;28(1):221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Siepen BM, Polymeris A, Shoamanesh A, Connolly S, Steiner T, Poli S, et al. Andexanet alfa versus non-specific treatments for intracerebral hemorrhage in patients taking factor Xa inhibitors—individual patient data analysis of ANNEXA-4 and TICH-NOAC. Int J Stroke. 2024;19(5):506–14. [DOI] [PubMed] [Google Scholar]
- 3.Oh ES, Schulze P, Diaz F, Shah K, Rios J, Silverman ME. The use of andexanet alfa and 4-factor prothrombin complex concentrate in intracranial hemorrhage. Am J Emerg Med. 2023;64:74–7. [DOI] [PubMed] [Google Scholar]
- 4.Vestal ML, Hodulik K, Mando-Vandrick J, James ML, Ortel TL, Fuller M, et al. Andexanet alfa and four-factor prothrombin complex concentrate for reversal of apixaban and rivaroxaban in patients diagnosed with intracranial hemorrhage. J Thromb Thrombolysis. 2022;53(1):167–75. [DOI] [PubMed] [Google Scholar]
- 5.Stevens VM, Trujillo TC, Kiser TH, MacLaren R, Reynolds PM, Mueller SW. Retrospective comparison of andexanet alfa and 4-factor prothrombin complex for reversal of factor Xa-inhibitor related bleeding. Clin Appl Thromb Hemost. 2021;27:10760296211039020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Irizarry-Gatell VM, Bacchus MW, De Leo EK, Zhang Y, Lagasse CA, Khanna AY, et al. The use of andexanet alfa vs. 4-factor prothrombin complex concentrates in the setting of life-threatening intracranial hemorrhage. Blood Coagul Fibrinolysis. 2024;35(3):94–100. [DOI] [PubMed] [Google Scholar]
- 7.Huttner HB, Gerner ST, Kuramatsu JB, Connolly SJ, Beyer-Westendorf J, Demchuk AM, et al. Hematoma expansion and clinical outcomes in patients with factor-Xa inhibitor-related atraumatic intracerebral hemorrhage treated within the ANNEXA-4 trial versus real-world usual care. Stroke. 2022;53(2):532–43. [DOI] [PubMed] [Google Scholar]
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