The principal finding of our study is that administration of TXA was associated with a reduction of the short-term mortality rate. IV administration of TXA also reduced short-term mortality in that subset of patients. TXA use led to a shorter bleeding time, lower bleeding volume, shorter length of hospital stay, and less requirements for intervention compared with the control. Administration of TXA was not associated with the recurrence of hemoptysis or increase in major or minor adverse effects.
Expectoration of large amounts of blood is associated with high morbidity and mortality. Advances in medical imaging, fiberscope technology, and interventional radiology have led to improved outcomes, with the reporting mortality rates ranging from 7–30% since 2000.(24–26) However, a strong recommendation regarding pharmacological treatment, such as antifibrinolytic agents for hemoptysis, does not exist.(27–29) TXA is an antifibrinolytic agent that is commonly used to control bleeding, and it has recently been proven a promising strategy to reduce mortality from hemoptysis.(13) Our study provided a comprehensive search from five databases and involved manual checking of the relative reviews and references to identify eligible studies. In total, 19943 patients were included, a number that was significantly larger than that of patients in the latest systematic review (n = 322).(28) We found that TXA administration consistently led to a 22% reduction in shorter-term morality. Moreover, a consistent reduction in short-term mortality by 22% was observed in a subset of patients receiving IV TXA. Additionally, according to the study by Wand et al., treatment with TXA through inhalation reduced the long-term mortality by 2%. In accordance with our findings, previous large-scale clinical trials have demonstrated that administration of TXA reduced the mortality of patients during uncontrolled post-partum hemorrhage and traumatic bleeding.(8, 9) This updated evidence, with more studies and more precise effect estimates (narrower CIs), reduces the uncertainty around the results.
Mild hemoptysis tends to stop spontaneously in some cases.(22) For hemoptysis greater than or equal to 1 liter per 24 hours, a mortality rate up to 58% was reported.(30) Among cases of fatal hemoptysis, the inciting cause of death is asphyxiation from inability to oxygenate or ventilate because of the hemorrhage flooding the airways.(31) The volume of the conducting airway is approximately 150 mL,(32) and a nonsignificant amount of pulmonary bleeding may hinder oxygenation before hemodynamics becomes unstable.(33) Therefore, it is critical to reduce the bleeding volume and foster bleeding cessation. Our study showed that patients in the TXA group showed earlier bleeding cessation by 24.3 hours compared with those in the control group. In addition, the results from three RCTs indicated that the administration of TXA reduced the bleeding volume. However, we did not observe any benefit of TXA in terms of the hemoptysis cessation rate. This could be attributed to the small number of the included studies with small sample sizes. Additional large clinical trials should be conducted to prove or disapprove our hypothesis.
The length of hospital stay is an important indicator of the patient quality of care and functional evaluation. Decreased length of hospital stay was associated with decreased medical costs in patients with hemoptysis.(15) Our study demonstrated that administration of TXA significantly reduced the length of stay by 1.94 days. In consistency with our observation, TXA administration to patients suffering from truncal and peripheral vascular trauma led to a 4-day shortening of hospital period, compared with placebo.(34) The explanation of this finding was that TXA provided better bleeding control, which may cause less morbidity during a hemoptysis episode, resulting in early discharge.
The requirement of embolization or surgical intervention to treat hemoptysis indicates additional medical efforts, risk of surgery, and anesthesia complications. A recent large RCT showed that TXA administration failed to reduce the requirement of surgical, endoscopic, or radiological intervention in patients with acute gastrointestinal bleeding.(35) In contrast, TXA reduced the requirement for Brace suture and laparotomy surgery in patients with postpartum hemorrhage.(8) There is little evidence about the pharmacological effect of hemoptysis on the need for hemostasis intervention. In our study, we observed that TXA reduced the requirement of further interventions by 62%.
A major concern with the application of TXA was the increase of thromboembolic events. TXA is associated with more than threefold increased odds of venous thromboembolism in patients with trauma.(36) Moreover, some studies showed that TXA administration led to a 6–11% increase in postoperative seizure among patients who underwent cardiac surgery.(37, 38) In addition, a case report had raised the concern that TXA administration led to pulmonary embolism in patients with chronic hemoptysis secondary to bronchiectasis.(39) However, in our study, no increased major adverse events were observed in the included RCTs.(13, 14, 21, 22) Further, TXA administration did not increase the incidence of thromboembolic events and seizure in a large-scale included observational study.(15) Therefore, TXA seemed safe for hemoptysis control.
Although our meta-analysis demonstrated the benefit of TXA for hemoptysis, it has several limitations. First, limited studies were included and the case numbers of the RCTs involved were relatively small. Second, observational studies were also included, which could have introduced a selection bias. Third, the length of treatment, dosage and form of TXA administration, and the definition of severity of hemoptysis varied among the studies, which may introduce clinical heterogeneities. However, significant statistical heterogeneities were observed only at the analysis of the hemoptysis cessation rate. Fourth, some factors, such as smoking, malignancy, pulmonary infection, and anti-coagulant drug use,(40–42) were associated with increased rate of mortality and hemoptysis recurrence. These confounding factors were not fully disclosed in some studies (Additional file 4). Moreover, most of the studies included all etiologies of hemoptysis, except one study that specifically dealt with tuberculosis-related hemoptysis. Therefore, whether the results of our study could be generalized to a specific population warrants further investigation. Finally, a funnel plot for assessing publication bias was not depicted owing to the small number of studies included.