Abstract
Aims:
Patients with epistaxis typically visit the emergency department for initial treatment. According to recent studies, tranexamic acid (TXA) is effective in the treatment of epistaxis. This study compared the therapeutic superiority of saline to that of 500 and 1000 mg doses of topical TXA for the treatment of anterior epistaxis.
Materials and methods:
This phase 4 clinical trial was a randomized, controlled, and double-blind trial. A total of 152 patients were divided into three groups. Group 1 was treated with 1000 mg TXA, Group 2 with 500 mg TXA, and Group 3 with saline.
Results:
Based on multinomial logistic regression analysis, the bleeding frequency at the 5th minute was 2.9 times and rebleeding status was 4.3 times less in Group 1 (1000 mg TXA) than in Group 3 (saline). There were no differences between the three groups in terms of side effects or salvage therapy.
Conclusion:
In addition to its superiority in treatment, 1000 mg of TXA is recommended because of the decreased rate of recurrent bleeding and low incidence of side effects.
Introduction
Background
Approximately 90% of nosebleeds are anterior hemorrhages, and the supplying area in the anterior septum, also known as Kiesselbach's plexus, is the source of anterior epistaxis. 1 Epistaxis is more common in children and the elderly, and these patients usually present to the emergency department for initial treatment. 1 Various methods are available to stop anterior epistaxis in the emergency department, including external pressure as well as treatment with decongestants (oxymetazoline), topical vasoconstrictors (phenylephrine, epinephrine), and local anesthetics (such as lidocaine).2,3 Anterior nasal packing (ANP) is a reasonable first choice to provide hemostasis, prevent drying, and protect the area from trauma in cases of bleeding that cannot be controlled by use of these treatment methods. 1 Despite the interventions applied in the emergency department, hemorrhage cannot be controlled in approximately 6% of the patients; thus, chemical cauterization, surgical ligation, and hospitalization are required.3–6
According to several recent studies, topical application of tranexamic acid (TXA) can be used effectively in the management of epistaxis.7,8 TXA is an antifibrinolytic drug used in the treatment and prophylaxis of bleeding associated with excessive fibrinolysis. It exerts a hemostatic effect by inhibiting plasminogen activation and providing fibrin-protecting activity in cases where fibrinolysis is pathologically increased. The method of application of TXA in epistaxis treatment is local application with nasal packing soaked in TXA ampoule content. For unstoppable or residual bleeding, 500–1000 mg three times a day is recommended.9,10
Although previous studies have reported that TXA provides effective bleeding control during active epistaxis and reduces the length of stay in the emergency department, the need for further treatment, and the rate of recurrent bleeding, there are insufficient randomized controlled double-blind studies on TXA.7,11 In addition, there is no consensus on the dose of the drug to be administered. Therefore, this study primarily focused on determining the appropriate dose of TXA for the treatment of anterior epistaxis.
Objectives
This study aimed to compare the therapeutic superiority of topical TXA doses of 500 and 1000 mg with that of saline in the treatment of anterior epistaxis.
Methods
Study design and setting
This randomized, double-blind, phase 4 study was conducted at a single center between July and December 2022. The center where the research was conducted was the emergency medicine department of a tertiary university hospital with an annual emergency admission of 250–300 thousand located in a metropolitan center with a population of approximately 5 million. Approval and permission for this phase 4 (IV) clinical trial were obtained from the local ethics committee (Decision No: 93 Date: 12/16/2021), Ministry of Health, and Turkish Medication and Medical Devices Agency (Decision No: E-85521274-000-1667768, Date: 06/28/2022). This study was enrolled in and endorsed by the American clinical trial registry (NCT06183918 at https://www.clinicaltrials.gov). No changes were made to the methods after commencement of the trial.
Participants
Among the patients aged 18 years and older who presented to the emergency department with epistaxis and agreed to participate in the study and could give written consent, those with posterior epistaxis; a history of nose or pharynx surgery in the last 3 months; facial and head trauma; unstable vital signs; recurrent bleeding who presented to the hospital for the second time; a history of allergy to TXA; subarachnoid hemorrhage; coagulation disorders such as hemophilia, hereditary telangiectasia, or von Willebrand disease; thromboembolic disease; and a history of convulsions or intracerebral processes, and those who were pregnant or lactating and wished to withdraw from the study at any stage of the study were excluded from the study. A total of 152 patients who did not meet the exclusion criteria were included in this study (Figure 1).
Consort flowdiagram of the study.
Variables
In this study, three different materials used to soak the gauze in nasal packing with gauze application, a treatment method for anterior epistaxis, were compared in terms of their superiority. Physicians and nurses participating in the study were given 2 h of theoretical and practical training on the design of the study and nasal packing application before the study. A simple randomization method was used. An assistant blinded to the study prepared the randomization schedule using a computer. First, those who met the study criteria, agreed to participate, and provided written consent were assigned to one of the treatment groups according to the next randomization. The references have been edited to ensure compliance with journal guidelines.
Until the end of the study, only those who prepared the randomization numbers knew the study numbers and matching groups. The treatment groups were defined as follows:
The research products, saline and TXA ampoules, contained 250 mg/2.5 ml of injectable solution, both in colorless, odorless, clean, and clear liquid form. Medications and medical supplies (gauze soaked with saline and TXA) to be used in the treatment, according to the randomization number, were prepared by a physician and nurse working in the emergency room who were informed about the research. The prepared ANP and medications were administered blindly by another emergency physician. The gauze soaked with saline or TXA was applied for 10 min and then removed. Another researcher, who was not responsible for the preparation and administration of the medication, recorded the data using a case report form (CRF). It was checked whether the bleeding continued at the 5th and 10th minutes after ANP and medication administration. In cases of bleeding lasting longer than 10 min, one of the standard epistaxis treatments (sponge-shaped nasal tampon or inflatable balloon-shaped nasal tampon) was applied as salvage therapy, and an otorhinolaryngology consultation was requested when necessary. In addition, the patients were followed-up for at least 1 h for possible side effects. Demographic data (age, sex); vital signs; use of anticoagulant and/or antiplatelet drugs; hemoglobin (Hgb), platelet (Plt), and international normalized ratio (INR) values of the cases; data of the applied procedure (5th and 10th minute bleeding control, necessity of salvage therapy); treatment-related side effects (administration site reaction, rash, itching, erythema, urticaria, hives, chest pain, dyspnea, nausea, vomiting, blackout, headache, dizziness); the need for otorhinolaryngology consultation; and whether recurrency developed within 24 h was recorded in the CRF. Participants were advised to inform the principal investigator by telephone if recurrent bleeding occurred within 24 h and to visit the emergency department again in case of recurrent and/or prolonged bleeding.
Data sources/measurements
The primary outcome of the study was bleeding control at the 5th and 10th minutes. Secondary outcomes were the need for salvage therapy, recurrent bleeding within 24 h, presence of side effects, and need for otorhinolaryngology consultation. There were no changes in trial outcomes after the trial commenced.
Bias
There is no tendency to prefer one person or thing to another or to favor that person or thing.
Study size
The sample size was calculated using G*Power version 3.1 (Heinrich-Heine Universitat, Dusseldorf, Germany). Based on similar studies previously conducted in the literature, the effect size was taken as 0.5. 12 Sample size comparison of independent groups was calculated with 0.05 alpha margin of error and 0.90 power, with an aim to reach at least 141 patients, 47 for each group. At the beginning of the study, we planned to stop the study if half of the targeted sample size could not be reached within 6 months.
Statistical methods
The Statistical Package for
Results
Participants
The study was terminated when sufficient sample size was reached. 152 patients who did not meet the exclusion criteria and met the inclusion criteria were included in the study. There were 51 patients in the 1000 mg TXA group (Group 1), 50 patients in the 500 mg TXA group (Group 2), and 51 patients in the group using gauze soaked with saline (Group 3). There were no dropouts or exclusions after randomization in any group.
Descriptive data
There were no differences between the groups in terms of age, sex, use of anticoagulants and/or antiplatelet drugs, history of epistaxis, Plt count, Hgb level, and INR values (p = 0.797, p = 0.093, p = 0.137, p = 0.211, p = 0.59, p = 0.499, and p = 0.06, respectively).
Outcome data
Among the study groups, the frequency of individuals with controlled bleeding at the 5th and 10th minutes was lower in Group 3 than in Groups 1 and 2. In each group, the frequency of bleeding at the 5th minute was higher than that at the 10th minute (Table 1).
Comparison of the individuals in the study group according to the bleeding status at the 5th and 10th minutes.
Chi-square test.
Statistically significant values (p < 0.05) are highlighted in bold.
Main results
As a result of the multinomial logistic regression analysis, which was created according to the factors of bleeding at the 5th minute, bleeding at the 10th minute, recurrence, and salvage therapy, which were found to be associated with the treatments applied as a result of the single analysis, the bleeding frequency at the 5th minute was 2949 times (CI: 1.018-8.538) lower in Group 1 than in Group 3 (Table 2).
Multinomial logistic regression analysis results with variables found to be associated with epistaxis.
SEa: Standard error; ORb: Odd's ratio; CIc: Confidence interval.
Statistically significant values (p < 0.05) are highlighted in bold.
Other analyses
Recurrent bleeding was detected more frequently in Group 3 than in Groups 1 and 2. There were no differences among the three groups in terms of side effects, salvage therapy, and necessity for otorhinolaryngology consultation (Table 3).
Comparison of recurrent bleeding and side effect statuses of the study groups.
Chi-square test.
Statistically significant values (p < 0.05) are highlighted in bold.
According to the results of the multinomial logistic regression analysis, which was created according to the 5th minute bleeding, 10th minute bleeding, recurrent bleeding, and salvage therapy factors, which were found to be related to the treatments applied according to the single analysis, rebleeding status was 4321 times (CI:1.095-17,042) and salvage therapy status was 3833 times (CI: 1548-9494) less frequent in Group 1 than in Group 3 (Table 4).
Multinomial logistic regression analysis results with variables found to be associated with epistaxis.
SEa: Standard error; ORb: Odd's ratio; CIc: Confidence interval.
Statistically significant values (p < 0.05) are highlighted in bold.
Discussion
Epistaxis is one of the most common otorhinolaryngology emergencies. 13 The clinical efficacy of topical application of the injectable form of TXA in the emergency treatment of epistaxis has been emphasized in recent studies. Topical application of the intravenous form of TXA has been shown to be superior to ANP in anterior epistaxis. 7 The novelty of our study is that it is the first randomized controlled trial to compare doses of TXA. The aim of this study was to determine the appropriate dose of TXA for anterior epistaxis treatment. It was shown that 1000 mg of TXA provided earlier bleeding control (at the 5th minute) and reduced the rate of recurrent bleeding and the need for salvage therapy.
A study by Zahed et al. in 2013 reported that the topical application of injectable TXA in anterior epistaxis treatment was better than ANP. In this study, in which 500 mg of TXA soaked with gauze was used, the nosebleed of the patients in the TXA group was controlled within 10 min at a higher rate than that of the ANP group (approximately 70% and 30%, respectively). 7 These results were similar to those of oral TXA. 14 In another study performed by Zahed et al. in patients taking antiplatelet drugs, bleeding was stopped within 10 min in 73% of the TXA-receiving group and 29% of the ANP-receiving group at the 10th minute. 11
In emergency departments, the treatment is rapid and effective. In our study, the 5th- and 10th-minute bleeding controls were higher in TXA-administered patients than in saline-administered patients. In our study, bleeding stopped at a rate of 82.4% in the 1000 mg TXA group at the 10th minute, 72% in the 500 mg TXA group, and 54.9% in the saline group. In the multinomial logistic regression analysis, bleeding at the 5th minute was 2949 times less in the group treated with 1000 mg of TXA than in the group treated with saline. The frequency of bleeding at the 5th minute was higher than that at the 10th minute in all three groups. The 1000 mg TXA may be a first-line treatment option in the emergency department for early bleeding control. However, more research is needed to determine its effectiveness, especially in cases of severe bleeding requiring surgical intervention.
In the study by Zahed et al., only ≈3% of patients in the TXA group had recurrent bleeding for 1 week compared with the rate of 11% in the ANP group. 7 In a study by Tibbelin et al. performed with TXA gel, recurrent bleeding rates were found to be 11% and 31%, respectively. 15 In another study conducted by Zahed et al., in patients with epistaxis and taking antiplatelet drugs, the rate of recurrent bleeding at the end of the first week was found to be lower than that in patients who received ANP. 11
In our study, the rate of recurrent bleeding within 24 h was evaluated. Recurrent bleeding was more common in the saline group than in the TXA group. Recurrent bleeding was 4321 times less frequent in the 1000 mg TXA group than in the saline group. We believe that TXA, as an antifibrinolytic agent, is effective in reducing the increased fibrinolytic activity reported in patients with epistaxis and provides fibrin-sparing activity in cases where fibrinolysis is pathologically increased, thereby providing lower recurrent bleeding rates.10,16
Topical TXA has been shown to have less than 30% systemic absorption, and there is evidence indicating that topical TXA can be used safely in patients with epistaxis without any complications.13,17 Although patients with a history of thrombosis were included in the CRASH-2 trial, no tendency toward thrombosis was detected. 10 In our study, there was no difference between the groups in terms of side effects. We believe that the absence of a side effect that would terminate the treatment even at 1000 mg doses of TXA and the absence of any difference in side effects will facilitate the reliability and compliance of the physician, and therefore increase the usability of TXA. In our study, the salvage therapy needs were higher in the saline-administered group than in the TXA-administered group, whereas no difference was observed in the otorhinolaryngology consultation status. We believe that this difference disappeared owing to the application of rescue treatment in the emergency department in the first place. Based on these data, TXA may be a first-line treatment option for the management of anterior epistaxis in emergency departments. It can also be used by ear, nose, and throat specialists together with advanced treatment methods in cases where first-line treatment methods fail.
Limitations
Patients presenting with epistaxis were not evaluated according to epistaxis severity scores. Therefore, the effectiveness of anticoagulants should be reconsidered, particularly in patients with severe bleeding. Patients with posterior epistaxis were not included in the study; therefore, we cannot comment on the effectiveness of TXA for posterior epistaxis. Both nosewings were compressed during the application, and although the practitioners were trained on this subject beforehand, the power of the press could not be measured clearly. This was a single-center study. It should be supported by multicenter studies with more patients.
Conclusions
TXA is an easily accessible drug with proven effectiveness in reducing blood loss in topical and intravenous forms. Local effects of TXA have been demonstrated; however, its application dose has not been determined. Although it is recommended to use TXA in the range of 500–1000 mg for epistaxis, 1000 mg is preferred when considering its safety regarding side effects and recurrent bleeding rates. It is superior to gauze soaked with TXA over saline in terms of clinical efficacy.
Supplemental Material
sj-doc-1-sci-10.1177_00368504241264993 - Supplemental material for Appropriate dose of tranexamic acid in the topical treatment of anterior epistaxis, 500 mg vs 1000 mg: A double-blind randomized controlled trial
Supplemental material, sj-doc-1-sci-10.1177_00368504241264993 for Appropriate dose of tranexamic acid in the topical treatment of anterior epistaxis, 500 mg vs 1000 mg: A double-blind randomized controlled trial by Cüneyt Arikan and Pınar Yeşim Akyol in Science Progress
Footnotes
Acknowledgements
We would like to thank the Izmir Katip Celebi University Atatürk Training and Research Hospital Emergency Medicine Clinic staff and Prof. Dr Fatih Esad Topal for their support during the study and Seval Caliskan Pala, who helped with the statistical analysis.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Research ethics and patient consent
Medical research was conducted according to the World Medical Association Declaration of Helsinki
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References
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