Effect of tranexamic acid on mortality in patients with haemoptysis: a nationwide study
Although tranexamic acid is widely used in patients with haemoptysis, whether it improves mortality has not been well investigated. The aim of this study was to evaluate the effect of tranexamic acid on in-hospital mortality among patients with haemoptysis.
This was a retrospective study using data from the Japanese Diagnosis Procedure Combination inpatient database. We identified all cases of emergency admission due to haemoptysis from July 2010 to March 2017. Patients were divided into two groups: a control group, and a tranexamic acid group (those who received tranexamic acid on the day of admission). The primary outcome was in-hospital mortality, with secondary outcomes of hospital stay length and total healthcare cost. The data were evaluated using a propensity score matching analysis.
Among 28,539 included patients, 17,049 patients received tranexamic acid and 11,490 patients did not. Propensity score analysis generated 9933 matched pairs. Compared to the control group, patients in the tranexamic acid group had significantly lower in-hospital mortality (11.5% vs. 9.0%; risk difference, − 2.5%; 95% confidence interval (CI), − 3.5 to − 1.6%), shorter hospital stays (18 ± 24 days vs. 16 ± 18 days; risk difference, − 2.4 days; 95% CI, − 3.1 to − 1.8 days), and lower total healthcare costs ($7573 ± 10,085 vs. $6757 ± 9127; risk difference, $− 816; 95% CI, $− 1109 to − 523).
Tranexamic acid may reduce in-hospital mortality among patients with haemoptysis requiring emergency admission.
KeywordsHaemoptysis Tranexamic acid Propensity score matching Cost-effectiveness
Intensive care unit
International Classification of Diseases Tenth Revision
Japan Coma Scale
Tissue plasminogen activator
Haemoptysis, defined as expectoration of the blood from the lower respiratory tract, is a potentially life-threatening condition with high morbidity and mortality [1, 2]. A recent French nationwide epidemiologic study that included more than 80,000 patients reported that 9.0% of patients who were hospitalised for haemoptysis required admission to the intensive care unit (ICU), and 8.7–10.1% of patients died during the admission. Hospital mortality was reported to be 5.9–7.1%, even after exclusion of deaths due to lung cancer, suggesting that haemorrhage control is essential .
Tranexamic acid is a synthetic derivative of the amino acid lysine, which blocks the interaction of plasminogen with the lysine residues of fibrin and exhibits an antifibrinolytic effect . Many randomised controlled trials and meta-analyses have reported that tranexamic acid reduces blood loss or transfusion requirements during elective operations, including cardiac, orthopaedic, oral, gynaecological, and urological surgeries [5, 6, 7], and may even prevent death in patients with significant traumatic or postpartum haemorrhage [8, 9, 10]. However, the impact of tranexamic acid on the volume or duration of haemoptysis remains unclear, since relatively few studies have investigated the effects of tranexamic acid among haemoptysis patients, and the results of these studies were inconsistent [11, 12, 13, 14]. Moreover, the potential mortality benefit of tranexamic acid in patients with haemoptysis has not yet been investigated.
We hypothesised that the administration of tranexamic acid would be effective for haemoptysis patients, as well as other acute haemorrhagic conditions, including trauma and postpartum haemorrhage. The aim of this study was to explore the effectiveness of tranexamic acid on mortality among patients with haemoptysis requiring emergency hospitalisation.
The study was approved by the Institutional Review Board of the University of Tokyo. The board waived the requirement for informed consent because of the anonymous nature of the data, as no information on individual patients, hospitals, or treating physicians was obtained.
We used the Japanese Diagnosis Procedure Combination inpatient database, which includes discharge abstracts and administrative claims data for more than 1200 acute care hospitals, and covers approximately 90% of all tertiary-care emergency hospitals in Japan. The database includes data on age, sex, body weight, body height, level of consciousness at admission, diagnoses, procedures, prescriptions, and discharge status. To optimise the accuracy of recorded diagnoses, the responsible physicians are obliged to record their diagnoses using standardised reference charts. The primary diagnoses are recorded using the International Classification of Diseases Tenth Revision (ICD-10) codes and text in the Japanese language. Furthermore, as the diagnostic records are linked to a payment system, the attending physicians are also required to report objective evidence for their diagnosis, for the purposes of treatment cost reimbursement . A previous study of these diagnostic and procedural records has established the validity of the database , with diagnostic specificity exceeding 96% and sensitivity of 50–80%. The specificity and sensitivity of procedures both exceeded 90%.
We identified all cases of emergency admission to ICUs or general wards due to haemoptysis in the database from July 2010 to March 2017.
All hospitalised patients who were diagnosed with haemoptysis (ICD-10 code R042) at admission to ICUs or general wards were included in the study. We did not include patients who developed haemoptysis after admission. We also excluded patients who were younger than 18 years of age, who died on the day of admission, who were discharged on the day of admission, or who were hospitalised electively. When patients were admitted with the code of haemoptysis more than once during the study period, we only used the data from the first admission.
Patients who received intravenous tranexamic acid on the day of admission were defined as the tranexamic acid group, with the remaining patients defined as the control group.
Covariates included age, sex, smoking history (non-smoker, current/past smoker, missing data), body mass index at admission, Japan Coma Scale (JCS) at admission , Charlson comorbidity index , comorbid atrial fibrillation (I48), comorbid venous thromboembolism (I26, I80, I82, O22, O87, O88), comorbid chronic kidney disease (N18, T82.4, Z49.2, Z99.2), ambulance use, teaching hospital, ICU admission on the day of admission, aetiologies of haemoptysis (ICD-10 codes listed in Additional file 1), examinations on the day of admission (acid-fast bacilli culture, bronchoscopy, oesophagogastroduodenoscopy, and computed tomography), and treatments on the day of admission (therapeutic embolisation, dopamine use, adrenaline use, noradrenaline use, transfusion, oxygenation, mechanical ventilation, and renal replacement therapy).
Body mass index was categorised as < 18.5, 18.5–24.9, 25.0–29.9, ≥ 30.0 kg/m2, or missing data. JCS status was categorised as alert consciousness, dizziness, somnolence, or coma. JCS status was shown to be substantially correlated with the Glasgow Coma Scale . The Charlson comorbidity index was scored according to the diagnoses for each patient and categorised as 0, 1, 2, 3, or≥ 4 . Comorbidity with atrial fibrillation or venous thromboembolism was collected to predict possible use of anticoagulant agents prior to admission. Data on comorbid chronic kidney disease were collected because the treatment guidelines for tranexamic acid suggest that it should be administered cautiously in patients with renal impairment . The aetiologies of haemoptysis were determined according to a previous epidemiologic study conducted using a French nationwide database .
The primary outcome was in-hospital mortality. The secondary outcomes were length of hospital stay, discharged to home, and total healthcare cost of the admission. As the costs were recorded in yen, we converted them into US dollars (110 yen = $1 USD). For the assessment of the safety of tranexamic acid, we also collected data on post-admission complications from thromboembolism (I21–I22, I26, I63, D735, N280, K763, K550, I74, I80, I822, I823, and I829) and seizure (R568, R252, R568, G403, and G400) .
A propensity score matching method was applied to compare the outcomes between the tranexamic acid group and the control group [21, 22]. A multivariable logistic regression model was employed to predict the patients’ propensity scores for tranexamic acid treatment. Predictor variables included age, sex, smoking history, body mass index, JCS, Charlson comorbidity index, comorbid atrial fibrillation, comorbid venous thromboembolism, comorbid chronic kidney disease, ambulance use, teaching hospital, ICU admission on the day of hospitalisation, aetiologies of haemoptysis, examinations on the day of admission, and treatments on the day of admission. One-to-one nearest neighbour matching without replacement was performed for the estimated propensity scores of the patients using a calliper width set at 20% of the standard deviation for the propensity scores [21, 22, 23]. To assess the performance of the matching, the baseline characteristics before and after propensity score matching were compared using absolute standardised differences, with an absolute standardised difference ≤ 10% considered to denote negligible imbalances between the tranexamic acid and control groups . We performed a propensity score matching using the STATA module of PSMATCH2 provided by Leuven and Sianesi .
Crude outcomes were compared in the unmatched cohort using Student’s t tests for continuous variables and chi-square tests for categorical variables. In the matched cohort, we used a generalised estimating equation approach for comparisons of the primary and secondary outcomes, accompanied by cluster-robust standard errors with individual hospitals as clusters . Risk differences and 95% confidence intervals (CIs) were calculated for the primary and secondary outcomes. These estimates were obtained by generalised estimating equation models using identity link functions, irrespective of the outcome types .
We conducted sensitivity analyses to confirm the robustness of the main result by applying different models, namely, propensity score adjustment analysis and stabilised inverse probability of treatment weighting analysis. First, for the overall cohort, we performed a multivariable regression model with generalised estimating equations accompanied by cluster-robust standard errors with hospitals used as the cluster variable. In this analysis, in-hospital mortality is defined as the dependent variable, and the intravenous tranexamic acid on the day of admission and the estimated propensity scores in the main analyses were used for covariates. Next, we applied a stabilised inverse probability of treatment weighting. The patient-specific stabilised inverse probability of treatment weighting was generated using the estimated propensity scores from the main analyses [28, 29].
As subgroup analyses, we evaluated treatment-by-covariate interactions to explore the heterogeneity of the treatment effects across the aetiologies: cryptogenic, tuberculosis, bronchopulmonary carcinoma, cystic fibrosis/bronchial dilatation, respiratory infection, and aspergillosis. Subgroup analyses were conducted in the propensity score-matched cohort only.
Continuous variables were presented as mean ± standard deviation, and categorical variables were described as numbers (%). All reported p values were two-sided, and p values < 0.05 were considered to be statistically significant. All analyses were performed using STATA/MP 15.0 software (StataCorp, College Station, TX, USA).
Role of the funding source
The funding source had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the study data and had final responsibility for the decision to submit for publication.
Patient characteristics at admission
Control (n = 11,490)
Tranexamic acid (n = 17,049)
Standardised difference (%)
Control (n = 9933)
Tranexamic acid (n = 9933)
Standardised difference (%)
72 ± 14
71 ± 14
72 ± 14
72 ± 13
Body mass index, kg/m2
Japan Coma Scale on admission
Charlson comorbidity index
Comorbidity of atrial fibrillation
Comorbidity of venous thromboembolism
Comorbidity of chronic kidney disease
Intensive care unit admission
Aetiologies of haemoptysis
Cystic fibrosis/bronchial dilatation
Examinations on the day of admission
Acid-fast bacilli culture
Treatments on the day of admission
Renal replacement therapy
Comparison of crude outcomes between the two groups
Control (n = 11,490)
Tranexamic acid (n = 17,049)
Length of hospital stay, days
19 ± 43
15 ± 17
Discharged to home
Total health care cost for the admission, USD
7686 ± 11,009
6715 ± 8524
Comparison of outcomes between the two groups in the matched cohort
Control (n = 9933)
Tranexamic acid (n = 9933)
Risk difference (95% CI)
− 2.5 (− 3.5 to − 1.6) %
Length of hospital stay, days
18 ± 24
16 ± 18
− 2.4 (− 3.1 to − 1.8)
Discharged to home
2.9 (1.7 to 4.1%)
Total health care cost for the admission, USD
7573 ± 10,085
6757 ± 9127
− 816 (− 1109 to − 523)
0.2 (− 0.2 to 0.6%)
In this study, we investigated the effectiveness of tranexamic acid among haemoptysis patients requiring emergency admission. The major finding was that the administration of tranexamic acid was associated with lower in-hospital mortality, after adjustment for confounding using propensity score matching. To the best of our knowledge, this was the first study to report an effect of tranexamic acid on mortality in patients with haemoptysis.
Although the association between haemoptysis and haemostatic abnormalities has not been well investigated, haemoptysis potentially causes fibrinolysis, since 90% of haemorrhages originate from ruptured bronchial arteries, which contain high levels of tissue plasminogen activator (t-PA) in their endothelial cells . Tranexamic acid is a well-known antifibrinolytic drug with established efficacy in prohibiting connections between fibrin and plasmin, which is activated by t-PA release from endothelial cells . Based on this mechanism, tranexamic acid has been used in patients with haemoptysis to reduce the amount of expectorated blood, ostensibly by decreasing the fibrinolytic activity and thereby improving the clinical outcomes.
Previous randomised controlled trials that investigated the effect of tranexamic acid on haemoptysis were small; the numbers of enrolled patients ranged between 46 and 66 [11, 12, 13, 14]. As such, one major strength of the current study was the larger sample size compared to previous studies. The absolute percentage of in-hospital mortality was 2.5% lower in the tranexamic acid group. Based on this figure, the number needed to treat in order to prevent one death from haemoptysis is 40. Furthermore, we believe that the number of propensity-matched patients in the present study (n = 19,866) is large enough to provide reasonably precise estimates of the effects of tranexamic acid.
Research in the field of severe trauma and postpartum haemorrhage strongly suggests that tranexamic acid reduces mortality when given within 3 h of onset, while it is no more effective when given later [9, 31]. Assuming this time-dependent effect modification in patients with haemoptysis, we conducted subgroup analyses investigating any difference in effect in six aetiology categories, including both acute and chronic onset diseases. However, the effect of tranexamic acid was not significantly different across acute diseases, such as respiratory infection and aspergillosis, and chronic conditions, such as tuberculosis, bronchopulmonary carcinoma, and cystic fibrosis/bronchial dilatation. Thus, we did not find sufficient evidence of a temporal effect of tranexamic acid in patients with haemoptysis. The association between the effects of tranexamic acid and timing of delivery should be investigated in future studies, controlling for the time from the onset of haemoptysis to the initiation of tranexamic acid treatment.
We also found that tranexamic acid was associated with shorter hospital stays and a higher probability of being discharged to home. These results were consistent with those in a recent randomised controlled trial, which reported that tranexamic acid inhalation was associated with significantly improved symptom resolution rates by 5days after admission, as well as shorter overall hospital stays . Moreover, tranexamic acid was associated with lower total healthcare costs for the admission, indicating that the use of tranexamic acid in patients with haemoptysis may be dominant from the standpoint of cost-effectiveness. We speculated that reduced length of stay likely contributed to the decreased hospitalisation cost. Because the cost of administering tranexamic acid has been reported to be universally low ($17.5 in Tanzania to $48.0 in the UK) , we believe that our results in Japan could be generalisable to other countries.
Neither thromboembolism nor seizure was significantly increased by tranexamic acid. Previous randomised controlled trials for other diseases also showed that the number of thromboembolisms was not significantly different between the tranexamic acid group and the placebo group [5, 8, 9]. On the other hand, the risk of seizure associated with tranexamic acid was considered to be dose-dependent . Administration of tranexamic acid at a dose of 100 mg/kg was significantly associated with seizure in one randomised controlled trial ; however, tranexamic acid did not increase seizure when it was used at a dose of 2 g or less . The reason for the lack of association between tranexamic acid and seizure in the present study may be that most patients in the tranexamic acid group received ≤ 2 g of tranexamic acid.
The present study has several limitations. First, the retrospective and observational nature of the study design leaves it open to potential bias and confounding. However, we adjusted for measured confounders by propensity score matching using the generalised estimating equation approach. Although all measured variables were well-balanced, and hospital characteristics were adjusted for by the generalised estimating equation model, we could not adjust for unmeasured potential confounders such as vital signs, chest X-ray findings, and volume of haemoptysis, as these variables were not included in the database . Second, it was also possible that anticoagulant-involved aetiology was not correctly recorded in the database, since its proportion was smaller than that of a previous study . We attempted to adjust for the use of anticoagulant agents by including atrial fibrillation and venous thromboembolism as baseline variables. Third, the time from the symptom onset to the initiation of the tranexamic acid administration was not measured. The difference in the effects of tranexamic acid based on the timing of treatment should be investigated in future studies. Finally, the results of this study might have affected by patient crossover across the treatment groups; 26.1% of patients in the control group received tranexamic acid treatment on the second day of symptoms or later.
This study, using a large nationwide database, suggested that administration of tranexamic acid was associated with reduced in-hospital mortality among patients with haemoptysis requiring emergency admission. This association should be confirmed in future randomised controlled trials.
This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (19AA2007 and H30-Policy-Designated-004) and the Ministry of Education, Culture, Sports, Science and Technology, Japan (17H04141).
TK and HO conceived, designed, and coordinated the study. TK and HO wrote the initial draft of the manuscript. HY contributed to the interpretation of the data and assisted in the preparation of the manuscript. HM, KF, HO, and HY critically reviewed the manuscript. HY provided a critical appraisal of the manuscript. All authors have read and approved the final manuscript.
The authors declare that they have no conflicts of interests. This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (19AA2007 and H30-Policy-Designated-004) and the Ministry of Education, Culture, Sports, Science and Technology, Japan (17H04141).
Ethics approval and consent to participate
The study was approved by the Institutional Review Board of the University of Tokyo. The board waived the need for informed consent, as this was a retrospective study.
Consent for publication
The Institutional Review Board waived the requirement for informed consent because of the anonymous nature of the data.
The authors declare that they have no competing interests.
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