Combined therapy with bronchial artery embolization and tranexamic acid for hemoptysis

Abstract

Background

While most previous studies have viewed tranexamic acid as a bridging or temporary therapy, our preliminary study offers insights into the combined therapy of antifibrinolytic agent with endovascular treatment for hemoptysis.

Purpose

To investigate the feasibility and safety of combined therapy, to analyze factors affecting the outcomes of combined therapy, and to compare the effectiveness of combined therapy between groups with different etiologies.

Material and Methods

Between January 2011 and December 2014, 64 patients (33 men, mean age 64.6 years) underwent combined therapy for hemoptysis. The median follow-up time was 14.7 months (range 174–2435 days). Patients were divided into a tuberculosis group (Group_TB, n=37) and a non-tuberculosis group (Group_non-TB, n=27).

Results

Embolotherapy was technically successful in 62/64 (96.9%) cases. The immediate clinical success rate was 96.8% (60/62). The short-term and long-term recurrence rates were 12.9% (n=8) and 19.4% (n=12), respectively. The one-, two-, and four-year recurrence-free survival rates were 61%, 49%, and 32%, respectively. There was no significant survival difference between the two groups. Suboptimal embolization was a significant risk factor for immediate clinical failure (odds ratio 29.624, P = 0.023). Optimal embolization (hazard ratio [HR] 0.199, P = 0.023) and older age (HR 0.956, P = 0.013) were significantly associated with lower recurrence risk.

Conclusion

Combined therapy is an effective and safe treatment modality for hemoptysis of various etiologies, with potential benefits for short-term recurrence vis-a-vis current literature evidence. Suboptimal embolization was the most important modifiable risk factor for treatment failure and recurrence after combined therapy.

Keywords

Bronchial artery embolization antifibrinolytic agent tranexamic acid hemoptysis tuberculosis

Introduction

Massive hemoptysis is a potentially life-threatening condition with a mortality rate > 50% (1 –4). Immediate, proper management is required in order to prevent catastrophic consequences, such as airway obstruction and asphyxia. Bronchial artery embolization (BAE) is the first-line treatment of choice for massive hemoptysis because it is non-invasive and is associated with minimal complications (5 –7). Although BAE achieves high technical and clinical success rates with immediate cessation of hemoptysis, a number of studies report the recurrence rate to be as high as 10%–55% (7,8). Recurrent bleeding after BAE may result from incomplete embolization, recanalization of embolized vessels, collateral circulation, or underlying disease progression (2,7,9). Relapsing hemoptysis usually requires repeat embolization, resulting in impaired quality of life and substantial financial cost.

Tranexamic acid (TXA) is an antifibrinolytic agent that has been used frequently in conservative hemoptysis management (10). While most previous studies have viewed TXA as a bridging or temporary therapy, our preliminary study offers insights into the potential benefits of combined antifibrinolytic agent and endovascular treatment therapy for hemoptysis (11 –13). The aims of the present study were: (i) to investigate the feasibility and safety of combined BAE and TXA therapy; (ii) to analyze factors affecting the outcomes of combined therapy; and (iii) to compare the effectiveness of combined therapy between groups with different etiologies.

Material and Methods

The Institutional Review Board of our hospital approved this retrospective single-center study and waived written informed consent for the use of clinical and imaging data.

Study participants and data collection

The inclusion criteria were as follows: (i) patients with hemoptysis who underwent combined therapy; (ii) available preprocedural computed tomography (CT) with enhancement; and (iii) available follow-up data. The exclusion criteria included patients who previously underwent BAE or combined therapy. From January 2011 to December 2014, 84 patients received combined therapy for hemoptysis. Among them, 20 were repeat treatments for recurrent hemoptysis. Finally, 64 consecutive patients were included in this study. Patients were divided into a tuberculosis (TB) group (Group_TB) and a non-TB group (Group_non-TB) according to etiology.

The data collection was based on patient medical records, which include outpatient, inpatient, and telephone follow-ups. The following data were collected for analysis: age, sex; underlying etiology; onset-to-treatment time interval; massive hemoptysis; duration of TXA administration; culprit artery hypertrophy grade; degree of embolization; and complications. In the present study, massive hemoptysis was defined as the production of ≥200 mL of blood over a 24-h period. Culprit artery hypertrophy was graded using a 4-point scale of angiographic flow in descending thoracic aortography, which is defined in Fig. 1 (14). In the present study, the major complications included neurologic damage, thromboembolic events, and hypersensitivity reactions. The minor complications included nausea/vomiting, chest pain, abdominal pain, and diarrhea.

Fig. 1.

(a–d) Representative angiographic images of different grades of culprit artery hypertrophy in descending thoracic aortography: (a) grade 0 = no visible flow through culprit artery; (b) grade 1 = faint opacification of culprit artery (black arrow) without hypertrophy; (c) grade 2 = definite opacification of hypertrophic culprit artery (white arrow); and (d) grade 3 = severe hypertrophy of culprit artery with definite parenchymal staining (white arrowhead).

Technical failure was defined as the inability of the operator to catheterize culprit arteries. Optimal embolization was defined as complete devascularization of all culprit arteries; suboptimal embolization was defined as any outcome less than complete devascularization (Fig. 2). Immediate clinical success was defined as complete resolution or clinically significant reduction in hemoptysis within two weeks of combined therapy. Recurrence referred to clinically significant hemoptysis occurring two weeks after combined therapy and was further divided into short-term recurrence (2 weeks–3 months) and long-term recurrence (>3 months).

Fig. 2.

(a–d) Representative angiographic images of optimal and suboptimal embolization. Optimal embolization: (a) selective right bronchial angiography shows arterial hypertrophied artery with intense parenchymal staining (black arrow) in right upper lung area; (b) complete devascularization of culprit artery is obtained on post-embolization angiography. Suboptimal embolization: (c) selective right inferior phrenic arteriography reveals tortuous artery with parenchymal staining (white arrow) and subsequent embolization was performed; (d) Selective right ninth intercostal angiography demonstrates subtle parenchymal staining (double white arrows). Embolization was not performed because an anterior spinal artery (white arrowheads) was also visualized to arise from the same intercostal trunk.

Combined treatment and procedural technique

The decision to conduct combined therapy was made through multidisciplinary collaboration between a pulmonary physician and an interventional radiologist. Before embolotherapy, a 500 mg/5 mL solution of TXA via intravenous injection was prescribed three times a day during hospitalization. After BAE, 500 mg/5 mL TXA solution three times a day was maintained until hemoptysis resolved, and TXA 250 mg to be taken orally three times a day was prescribed for one week at discharge.

Any hypertrophied bronchial arteries or non-bronchial systemic collaterals were carefully reviewed on preprocedural imaging. All procedures were performed under local anesthesia with 2% lidocaine hydrochloride. Patient vital signs were monitored throughout the procedure. A 5-F vascular sheath was placed in the right common femoral artery. Thoracic aortography was performed using a 5-F pigtail catheter and abnormal culprit arteries were evaluated. After catheterization, selective angiography was performed. The finding of active contrast extravasation was considered as a direct sign on angiography. The indirect signs that indicate a site of bleeding include hypertrophic and tortuous bronchial arteries, neovascularity, hypervascularity, shunting into the pulmonary artery or vein, and bronchial artery pseudoaneurysm (1).

Superselective embolization was performed on culprit arteries via a 2.0–3.0-F microcatheter with special attention to avoid inadvertent embolization of spinal arteries. In each patient, embolization extent was determined via a combination of CT, bronchoscopic, and angiographic findings and clinical correlations. Polyvinyl alcohol (PVA) particles (size = 355–500 µm or 500–710 µm, Contour; Boston Scientific, Wayne, NJ, USA) were used as embolic materials at our institution.

Statistics

For descriptive statistics, continuous variables are presented as the mean ± SD, and categorical variables are presented as absolute and relative frequencies. To compare baseline characteristics between the two groups, the Wilcoxon rank-sum test was used for continuous variables, and the chi-squared test or Fisher’s exact test was used for categorical variables. Firth’s penalized likelihood logistic regression analysis was used to determine the risk factors affecting immediate clinical failure of combined therapy. Odds ratios (ORs) and 95% confidence intervals (CIs) are presented in the logistic regression results.

Recurrence-free survival rates were analyzed and compared using Kaplan–Meier survival analysis. A Cox proportional hazards regression model was used to analyze the risk factors affecting recurrent hemoptysis, and the hazard ratio (HR) and 95% CI were calculated. Factors explored in logistic and Cox regression analyses included underlying TB, age, sex, massive hemoptysis, onset-to-treatment time interval, duration of TXA administration, culprit artery hypertrophy grade, and degree of embolization. To test multicollinearity, we calculated the variance inflation factor (VIF). A P value < 0.05 was considered statistically significant. All statistical analyses were executed using SAS (version 9.4; SAS Institute, Cary, NC, USA).

Results

Patients

Sixty-four patients (33 men, 31 women; mean age = 64.6 years) were included in the study. The median follow-up time was 14.7 months (range = 174–2435 days). The most common underlying disease was TB (Group_TB, n = 37 patients). Group_non-TB etiologies (n = 27) included non-TB mycobacteria infection (n = 1), aspergillosis infection (n = 4), malignancy (primary lung cancer [n = 5], metastasis [n = 2]), bronchiectasis (n = 12), pulmonary thromboembolism (n = 1), and unknown causes (n = 2). Patient data from both study groups are summarized in Table 1. No statistically significant differences were observed with regard to age, sex, massive hemoptysis, onset-to-treatment time interval, duration of TXA administration, culprit artery hypertrophy grade, or degree of embolization. However, there was a significant difference in massive hemoptysis (P = 0.015) between the two groups.

Table 1.

Baseline characteristics of Group_TB and Group_non-TB.

Variable	Group_TB (n = 37)	Group_non-TB (n = 27)	P value
Age (years)	65.95 ± 12.71	62.78 ± 12.33	0.430
Sex (male)	18 (48.65)	15 (55.56)	0.585
Massive hemoptysis	25 (67.57)	10 (37.04)	0.015
Onset-to-treatment time interval (days)	2.41 ± 1.88	3.52 ± 3.71	0.330
TXA administration duration (days)	4.22 ± 2.57	5.3 ± 4.64	0.714
Culprit artery hypertrophy grade			0.630
Grade 0	1	2
Grade 1	4	3
Grade 2	26	18
Grade 3	6	4
Degree of embolization			0.266
Suboptimal	3	5
Optimal	34	22

Values are given as n (%) or mean ± SD.

TXA, tranexamic acid.

Clinical outcomes of combined therapy

On angiography, all patients had at least one indirect sign of bleeding. The most common indirect angiographic finding was hypertrophy of the culprit artery (61/64, 95.3%). No patients showed direct signs of contrast extravasation. The technical success rate of embolization was 96.8% (62/64), including optimal (n = 56) and suboptimal (n = 6) embolization. The following arteries were embolized: right bronchial artery (n = 47); left bronchial artery (n = 38); right intercostal artery (n = 10); left intercostal artery (n = 8); right internal mammary artery (n = 3); left internal mammary artery (n = 4); right inferior phrenic artery (n = 3); left inferior phrenic artery (n = 8); left lateral thoracic artery (n = 1); and left thyrocervical trunk (n = 1).

The two patients who experienced unsuccessful embolization had challenging anatomy due to acute angulation and atherosclerotic changes in the aneurysmal aorta; thus, superselective catheterization of the culprit artery was impossible. The immediate clinical success rate of our study was 96.8% (60/62). Recurrent hemoptysis after combined therapy occurred in 20/64 (31.3%) patients. The short-term and long-term recurrence rates were 12.9% (n = 8) and 19.4% (n = 12), respectively. No patient suffered major complications after combined therapy. Five patients complained of mild chest pain that subsided with conservative management.

The overall survival rate of the study population was 95.3% (61/64). One patient died from recurrent hemoptysis three months after treatment, and the other two patients died of unknown causes four months and one year later. The one-, two-, and four-year recurrence-free survival rates during the study period were 61%, 49%, and 32%, respectively (Fig. 3). The Kaplan–Meier estimate showed no significant survival difference between Group_TB and the Group_non-TB patients.

Fig. 3.

Kaplan–Meier curves demonstrate the overall recurrence-free survival rate (a) and recurrence-free survival rate for subgroups (b).

Regarding factors influencing immediate clinical success, univariable and multivariable logistic regression analyses indicated that suboptimal embolization (OR = 29.624, 95% CI = 1.612–544.310, P = 0.023) was significantly associated with immediate clinical failure (Table 2). Regarding factors influencing recurrent hemoptysis, optimal embolization (HR = 0.199, P = 0.023) and older age (HR = 0.956, P = 0.013) were significantly associated with lower recurrence risk (Table 3). The values of VIF for all variables were < 2, indicating there was no multicollinearity.

Table 2.

Logistic regression analysis of risk factors associated with immediate clinical failure.

	Univariable		Multivariable
Variable	OR	P value	OR	P value
Underlying TB	1.392	0.727	0.567	0.680
Age	1.028	0.441
Sex	2.333	0.408
Massive hemoptysis	0.119	0.166	0.054	0.096
Onset-to-treatment time interval	0.958	0.769
Duration of TXA administration	0.903	0.323
Culprit artery hypertrophy grade	2.387	0.151	1.983	0.451
Degree of embolization	23.546	0.004	29.624	0.023

Multi-collinearity was examined using variance inflation factor.

OR, odds ratio; TB, tuberculosis; TXA, tranexamic acid.

Table 3.

Cox proportional hazards regression model analysis of risk factors associated with recurrent hemoptysis.

	Univariable		Multivariable
Variable	HR	P value	HR	P value
Underlying TB	1.531	0.329	1.873	0.195
Age	0.966	0.044	0.956	0.013
Sex	1.345	0.475
Massive hemoptysis	1.025	0.953	0.847	0.727
Onset-to-treatment time interval	1.034	0.687
Duration of TXA administration	0.985	0.807	0.983	0.788
Culprit artery hypertrophy grade	1.168	0.611
Degree of embolization	0.387	0.128	0.199	0.024

Multi-collinearity was examined using variance inflation factor.

HR, hazard ratio; TB, tuberculosis; TXA, tranexamic acid.

Discussion

Although antifibrinolytic and vasoconstrictive agents are frequently used as medications for hemoptysis, the two agents may produce conflicting pharmacodynamics when used in combination with endovascular treatment (10). Vasoconstrictors such as vasopressin could help reduce hemoptysis by constricting blood vessels and thereby limiting tissue perfusion. However, the use of intravenous vasoconstrictors alongside BAE may hamper effective embolization by: (i) obscuring the bleeding focus, which could result in false-negative findings on catheter angiography; and (ii) decreasing culprit artery diameter, which could complicate cannulation of the culprit artery or lead to incomplete embolization (15,16).

On the other hand, antifibrinolytic agents such as TXA stabilize clots and facilitate formation of clots by competitively inhibiting plasminogen, which could possibly reinforce the effect of embolotherapy. At present, a consensus has not been reached on the benefits of antifibrinolytic agents (11 –13). A Cochrane systematic review that included two randomized controlled trials found insufficient evidence to determine whether antifibrinolytic agents should be used to treat hemoptysis, but limited evidence suggests a reduction in bleeding time (11). A recent randomized controlled trial showed that TXA decreased the severity of hemoptysis and may be used as a bridge therapy to other interventions (13). In the present study, we suggest that combined therapy of antifibrinolytic agent and endovascular treatment may be used to reduce the risk of relapsing hemoptysis.

Embolotherapy has become an established and safe treatment option to manage life-threatening hemoptysis. Its high technical success rate and clinical effectiveness have been well described. According to previous studies with BAE, the technical success rate is in the range of 81%–100%, and the immediate success rate is in the range of 82%–98% (5 –8). The risk factors for immediate clinical failure after BAE have not been thoroughly investigated, but massive hemoptysis and some angiographic findings were thought to be possible candidates (17). In the present study, the technical success rate (96.9%) and the immediate clinical success rate (96.8%) of combined therapy demonstrate satisfactory performance. Suboptimal embolization was significantly associated with immediate clinical failure, but massive hemoptysis and culprit artery hypertrophy grade were not statistically significant.

The recurrence rate after BAE remains high. The short-term hemoptysis control rate (within three months) was reported to be in the range of 76.2%–79.5%, and the long-term hemoptysis control rate was in the range of 51%–76.1% after one year, 55.7%–62.9% after two years, and 35.9%–51.4% after three years (7,8,18). There is very little evidence regarding the mechanism of recurrent hemoptysis after BAE (9). Although delayed recurrences may be attributed to neovascularization or underlying disease progression, early recurrences seem to be related to suboptimal embolization or recanalization. The mechanism of recanalization is closely associated with the biological properties of embolization particles. An experimental animal study with spherical embolization agents showed that recanalization was pronounced with PVA particles and typically occurred 4–12 weeks after embolization, which is consistent with early recurrence (19). However, although embolotherapy was performed using contour particles in this study, the short-term hemoptysis control rate (87.5%) was even higher than that estimated in previous studies (7). The relatively higher short-term disease control rate in our study could be partly explained by the enhancing effect of TXA during the embolization process.

Suboptimal embolization was the most important risk factor for recurrent hemoptysis as well as immediate clinical failure. Among six patients who experienced suboptimal embolization, immediate hemoptysis control was achieved in four patients and short-term recurrence occurred in only two patients. In these patients, embolization could be achieved at least one artery among multiple culprit arteries. In this regard, few patients may demonstrate favorable outcomes.

Embolotherapy and antifibrinolytic agents are both safe treatment options for hemoptysis. Adverse effects caused by TXA have not been reported in three previous randomized control trials (11,13). The major complication rate after BAE seems negligible, with a median incidence of 0.1% (range = 0%–6.6%) (3,7). According to a previous systematic review, superselective catheterization was frequently performed in recent studies, resulting in decreasing complications (7). In the present study, no major complications occurred in any of the patients; therefore, combined therapy also appears to be a safe treatment option.

A Cochrane systematic review with TXA pooled two randomized controlled trials: one for hemoptysis caused by TB and the other for hemoptysis from a variety of causes (11). Despite the use of the same antifibrinolytic agent, differences in outcomes were observed between the two studies. The etiologic factor was considered one of the major factors responsible for the different results. Pulmonary TB is the most common etiology of hemoptysis among non-Western countries (1,18). The most frequent diseases causing massive hemoptysis are TB, bronchiectasis, and lung cancer (5,20). In the present study, TB was the single most common etiology, and massive hemoptysis was significantly more frequent (P = 0.015) in Group_TB than in Group_non-TB. However, there was no significant difference in the clinical results of combined therapy between the two groups. Several studies have examined the effectiveness of BAE according to various etiologies, demonstrating that aspergillosis and malignant disease are generally associated with poor outcomes (5,21,22). The results of our study might be explained by the small proportion of patients with malignancy or aspergillosis (11/27, 40.7%). Among the seven patients with malignancy, immediate hemoptysis control failed in two and recurrent hemoptysis occurred in two. However, among four patients with aspergillosis, there was no treatment failure or recurrence.

The present study has some limitations. Because of its retrospective nature, bias could have been introduced during data collection and analyses, and there may be missing factors that affected the performance of combined therapy. Since clinical failures of current study are rare, larger numbers of participants are required to generalize our preliminary findings. We failed to serve control arms; therefore, it cannot be elucidated how much each therapy contributed to hemostasis in the current study. Further prospective randomized controlled trials with larger sample sizes are needed to validate our study results.

In conclusion, combined therapy with BAE and TXA is an effective and safe treatment for hemoptysis of various etiologies, with potential benefits for short-term recurrence vis-a-vis evidence in the current literature. Suboptimal embolization was the most important modifiable risk factor for treatment failure and recurrence in patients who received combined therapy.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Hyoung Nam Lee

Sung Ki Cho

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