Background: Thrombolytic agents and anticoagulants are the two classes of medication used in the treatment of acute pulmonary embolism (PE). There is continuous renewal and iteration of thrombolytic agents, and the efficacy and adverse effects of different agents have different effects on PE due to their different mechanisms of action. Objectives: The aim of the study was to evaluate the efficacy and safety of different thrombolytic agents in the treatment of all types of acute PE: hemodynamically unstable PE (massive PE) and hemodynamically stable PE (submassive PE and low-risk PE), using a network meta-analysis. Methods: A search was conducted of the following databases: PubMed, The Cochrane Library, Embase, and Web of Science to collect randomized controlled trials (RCTs) comparing thrombolytic agents with heparin or other thrombolytic agents in patients with acute PE; the clinical outcomes included patient mortality, recurrent PE, pulmonary artery systolic pressure (PASP) after treatment, and major and minor bleeding. The measurement duration of outcome indicators was the longest follow-up period. Thereafter, a network meta-analysis was performed using a Bayesian network framework. Results: A total of 29 RCTs (3,067 patients) were included, of which 6 studies (304 patients) were massive PE, 14 studies (2,173 patients) were submassive PE, 1 study (83 patients) included massive and submassive PE, and 8 studies (507 patients) were PE of unknown type. The treatment regimens included thrombolytic therapy (alteplase, reteplase, tenecteplase, streptokinase, and urokinase) and anticoagulant therapy alone. The results showed that the mortality using thrombolytic agents (except tenecteplase) was significantly lower compared with heparin. The recurrence of PE with alteplase was significantly lower compared with heparin (RR = 0.23, 95% CI, 0.04, 0.65). The PASP after using alteplase was significantly lower compared with heparin (mean difference = −11.36, 95% CI, −21.45, −1.56). Compared with heparin, the incidence of minor bleeding associated with tenecteplase was higher (RR = 3.27, 95% CI, 1.36, 7.39); compared with streptokinase, the incidence of minor bleeding associated with tenecteplase was higher (RR = 3.22, 95% CI, 1.01, 11.10). Conclusion: For patients with acute PE, four thrombolytic agents (alteplase, reteplase, streptokinase, and urokinase) appeared to be superior in efficacy compared with anticoagulants alone due to a reduction in mortality and no increase in bleeding risk. Alteplase may be a better choice because it not only reduced mortality but also reduced PE recurrence rate and treated PASP. Tenecteplase did not reduce mortality compared with anticoagulants alone and may not be a good choice of thrombolytic agent due to an increase in minor bleeding compared with streptokinase and anticoagulants alone. Thrombolytic drugs should be rationally selected to optimize the thrombolytic regimen and achieve as good a balance as possible between thrombolysis and bleeding.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Venous thromboembolism, which clinically presents as deep vein thrombosis or pulmonary embolism (PE), ranks third after myocardial infarction and stroke in deaths due to cardiovascular syndrome all over the world [1]. The incidence of PE has increased annually over the past few decades, with an estimated annual incidence of 39∼115 per 100,000 people [2]. PE mortality increases exponentially with patient age, resulting in mortality rates as high as 3%∼8% and 25%∼52% for submassive PE and massive PE, respectively [3]. Recent epidemiological data shows that the 30-day morbidity and mortality rate in patients with high-risk acute PE is as high as 22% [4]. In addition to the early consequences of PE, post-PE injury is still the main late complication of acute PE, which is related to decreased functional ability and increased medical expenditure [5, 6].

Thrombolytic agents and anticoagulants are the main drugs for the treatment of PE. International guidelines recommend reperfusion therapy for patients with hemodynamic instability or high-risk PE [2, 7]. Current studies have shown that thrombolytic therapy can reduce mortality and the recurrence of PE in high-risk PE patients, but it will also increase the risk of bleeding [8, 9]. The risk-benefit ratio of thrombolytic therapy seems to be very narrow and needs further research. Therefore, the use of initial thrombolysis or anticoagulation is still controversial in the medical community [10]. There is continuous renewal and iteration of thrombolytic agents, and different agents have different effects on acute PE in relationship to efficacy and adverse effects due to their different mechanisms of action. Clarification of the effects of different thrombolytic agents on acute PE will be of great assistance in their clinical application.

However, there has been no systematic comparison and evaluation of the effects of different thrombolytic agents on acute PE in previous studies, and their therapeutic effects and risk-benefit ratios are still unknown. Therefore, in this study, we aimed to do a systematic review and network meta-analysis to inform clinical practice by comparing different thrombolytic agents for the treatment of adults with acute PE.

Materials and MethodsData Sources and Searches

The study protocol was registered in the PROSPERO database (ID of CRD 42022304127). We searched PubMed, The Cochrane Library, Embase, and Web of Science from the inception to January 6, 2022, using a combination of text-free terms and their corresponding Mesh terms. We used the search terms “pulmonary embolism” OR “Pulmonary Embolism” OR “Pulmonary Embolisms” OR “Pulmonary Thromboembolisms” OR “Pulmonary Thromboembolism” OR PE combined with a list of all included thrombolytic agents. There was no limitation on language or publication date. Eligible studies were also searched for by manually checking the reference lists of the included studies. Details of the search strategy for PubMed are shown in the online supplementary materials (see www.karger.com/doi/10.1159/000527668 for all online suppl. material).

Study Selection

Studies were included in this review based on the following criteria. (1) The studies must be randomized controlled trials (RCTs). (2) The study population included patients with all types of acute PE: hemodynamically unstable PE (massive PE), hemodynamically stable PE (submassive PE, and low-risk PE); the terms massive or submassive PE are used interchangeably with the terms high-risk or intermediate-risk PE, respectively [11, 12]. (3) The comparator should be a thrombolytic agent and an anticoagulant drug for PE directly compared with each other, the combination of a thrombolytic agent, and an anticoagulant drug compared with an anticoagulant drug alone, as well as different thrombolytic agents compared with each other. (4) Different categories of medicines must be used in different groups of patients, and only one type of regimen can be used during the trial by one group of patients. (5) Trials must report at least one outcome of interest (see below). We excluded trials where patients were undergoing surgical thrombectomy or ultrasound-accelerated thrombolysis. For studies published more than once, we included only the report with the most informative and complete data.

Outcome Measures

The primary outcome of this study was the efficacy of the thrombolytic agents, including patient mortality, recurrent PE, and pulmonary artery systolic pressure (PASP) after treatment. The secondary outcome was safety, including major bleeding and minor bleeding. Major bleeding was defined as intracranial bleeding or bleeding involving hemodynamic impairment that required intervention; minor bleeding was defined as bleeding requiring intervention but not resulting in hemodynamic impairment or other bleeding. The measurement duration of outcome indicators was the longest follow-up period.

Data Extraction and Quality Assessment

After duplicate data elimination, two independent reviewers (H.-Y.L. and Y.-B.W.) screened the titles and abstracts of the retrieved records against inclusion and exclusion criteria and read the full text for possible eligibility. Disagreements were resolved through consultation with another reviewer. Data extraction was performed by two independent reviewers including the first author, year of publication, date of registration, stage of PE, sample size, age, sex, treatment regimen, and outcome indicators (mortality, recurrent PE, PASP, major bleeding, minor bleeding). For each treatment, we combined outcome data from all approved doses into one intervention group. If a study reported outcomes at different time points, we extracted data from the report for the longest duration of intervention for each outcome. If a study contained two or more arms, we treated them as separate comparisons. If a study included two different treatment regimens for the same drug, we selected the treatment that was closest to the currently recommended regimen.

Two independent reviewers assessed the risk of bias using the Cochrane Risk of Bias Tool 2.0 (RoB 2.0) [13]. Disagreements were solved through discussion.

Statistical Analysis

We fitted our models in R using the BUGSnet package (version 1.1.1) [14]. We estimated the summary risk ratio (RR) for dichotomous outcomes and the mean difference for continuous outcomes. The study effect sizes were then synthesized using a random-effects network meta-analysis model using a Bayesian network frame. Heparin was selected as the reference treatment. We drew network evidence maps for all outcomes. We conducted a network meta-analysis by fitting a generalized linear model with a complementary log-log link function and binomial likelihood function. A multiple treatment comparison was conducted using a Monte Carlo Markov Chain (MCMC) model. We conducted four MCMC chains simultaneously. We specified a burn-in of 1,000 iterations followed by 10,000 iterations with 1,000 adaptations. The deviance information criterion value and a visual examination of the leverage plots were used to assess heterogeneity between studies. Two different models were run for each outcome: random-effect consistency model and random-effect inconsistency model. The deviance information criterion value provided a measure of model fit that reduces the complexity of the model; a lower deviance information criterion value indicated a better model fit. If the deviance information criterion values were similar between the random-effect consistency and random-effect inconsistency models, the simpler random-effect consistency model was used. The random-effect consistency model was used if the deviance information criterion value of the random-effect consistency model was at least 5 lower than that of the random-effect consistency model. If the deviance information criterion value was not displayed, we visually compared the leverage plot and selected a model with fewer outliers in the leverage plot. The potential scale reduced factor (PSRF) was used to judge the convergence of the models. When the PSRF value was between 1.00 and 1.05, it indicated that the convergence of the iteration effect was good; otherwise, iterative calculations with larger parameters were used until the PSRF value was between 1.00 and 1.05. We estimated the probabilities of each treatment being at each rank for each intervention and outcome. To rank the treatments for each outcome, we used the surface under the cumulative ranking curve (SUCRA) and the mean ranks; the larger value of SUCRA implied a higher hierarchy [15].

To assess the presence of inconsistency, we fitted a network meta-analysis model like the one previously described, assuming inconsistency. We obtain leverage plots for the consistency model and inconsistency model. The deviance information criterion value and visual examinations of the degree of heterogeneity in the leverage plots were compared. If the deviance information criterion value of the consistency model is small, it can indicate that it is consistent. We also plotted the posterior mean deviation contributions for each data point to assess the inconsistency [16]. The comparison-adjusted funnel plots were made by Stata 17.0 to assess the publication bias.

ResultsStudy Selection and Basic Characteristics

The literature search identified 3,837 articles. After eliminating 1,226 duplicate articles, 2,611 articles remained. After reading the titles and abstracts, 2,544 articles were excluded. Based on the inclusion and exclusion criteria, 29 RCTs including 3,067 patients were finally included [17-45]. PE types included in the study were as follows: 6 studies including 304 patients [19, 30-33, 35] reported massive PE; 14 studies including 2,173 patients [17, 18, 20-25, 27-29, 34, 37, 38] reported submassive PE; 1 study including 83 patients [26] reported massive and submassive PE; and 8 studies including 507 patients [36, 39-45] reported PE of unknown type. The treatment regimens included thrombolytic therapy (alteplase, reteplase, tenecteplase, streptokinase, and urokinase) and anticoagulant therapy alone. All included literature showed that the baseline of patients in the two groups was consistent; overall, we deemed the sample similar enough to synthesize jointly. The processes and results of literature screening are shown in Figure 1. Table 1 provides the baseline characteristics of the included trials. The measurement time of each outcome in the included studies is shown in online supplementary Table 1.

Table 1.

The clinical characteristics of including articles

Fig. 1.

Flow chart of the identification process of relevant articles.

Bias Risk Assessment

Among the 29 RCTs included, high risk of bias was rarely seen in any field. Most studies did not describe the method of randomization, such as the method of generating the randomization sequence, or the method of assigning concealment, so ranking assessment as unclear was common. In addition, most studies did not involve patient or investigator blinding and did not report details of the blinding of outcome assessors. Regarding overall bias, only 8 articles were considered to have a low risk of bias. The results of bias risk assessment are shown in Figure 2a, judgment of the percentage of items with the risk of bias in all included studies is shown in Figure 2b.

Fig. 2.

Summary of the RoB 2.0 assessment. a Summary of the risk-of-bias (RoB 2.0) assessment for each included study according to five domains and the overall RoB 2.0. The colors represent the level of RoB 2.0: green indicates a low risk of bias; yellow indicates some concerns; and red indicates a high risk of bias. b Judgment of the percentage of items with the risk of bias in all included studies.

Consistency

By evaluating the inconsistency of different outcome indicators, we found that the deviance information criterion value for the consistency model was marginally smaller than for the inconsistency mode. Visual examination of the leverage plots showed that the dispersion of the consistency model was small. Therefore, in this study, the consistency model was used for all analyses. The PSRF value was between 1.00 and 1.05, which indicated that the convergence of the iteration effect was good. The deviance information criterion value and posterior mean deviation contributions for the consistency model and the inconsistency model are shown in online supplementary Figures 1 and 2.

Results of Network Meta-analysis

The qualified comparison networks for primary and secondary results are shown in Figure 3. The SUCRA values of different outcomes are shown in Figure 4, SUCRA values and ranking of each outcome index are shown in Table 2. Figure 5 shows the league table for comparisons of outcomes of mixed treatment. The ranking probability histogram for different outcomes is shown in online supplementary Figure 3.

Table 2.

Surface under the cumulative ranking curve (SUCRA) value and ranking of different outcomes

Fig. 3.

Network of treatment comparisons of outcomes. a Mortality. b Recurrent PE. c PASP. d Major bleeding. e Minor bleeding.

Fig. 4.

Surface under the cumulative ranking curve (SUCRA) of different outcomes. a Mortality. b Recurrent PE. c PASP. d Major bleeding. e Minor bleeding.

Fig. 5.

League table heatmap showing mixed treatment comparisons for outcomes. The values in each cell represent the treatment effect (and 95% credible intervals) of the treatment on the top, compared to the treatment on the left. A double asterisk indicates statistical significance. a Mortality. b Recurrent PE. c PASP. d Major bleeding. e Minor bleeding.

Mortality

There were 25 studies [17, 18, 21, 23-35, 37-45] including 2,803 patients reporting mortality. All studies were two-arm studies, and the network evidence map is shown in Figure 3a. The weight of each study is shown in online supplementary Table 2. The results of the network meta-analysis showed that the mortality using reteplase was significantly lower compared with heparin (RR = 0.07, 95% CI, 0.00, 0.87); the mortality using streptokinase was significantly lower compared with heparin (RR = 0.21, 95% CI, 0.04, 0.52); the mortality using urokinase was significantly lower compared with heparin (RR = 0.22, 95% CI, 0.06, 0.55); and the mortality using alteplase was significantly lower compared with heparin (RR = 0.41, 95% CI, 0.16, 0.84). There was no statistically significant difference in mortality when making comparisons between different thrombolytic agents. The SUCRA values are shown in Figure 4a, and the league table is shown in Figure 5a.

Recurrent PE

There were 17 studies [18, 21, 23-25, 27-29, 31, 32, 34, 35, 37, 38, 41, 43, 45] including 2,433 patients reporting recurrent PE. All the studies were two-arm studies, and the network evidence map is shown in Figure 3b. The weight of each study is shown in online supplementary Table 2. Compared with heparin, alteplase resulted in a statistically significant reduction in recurrence of PE, and the difference was statistically significant (RR = 0.23, 95% CI, 0.04, 0.65). There was no statistically significant difference in the recurrence of PE when comparing different thrombolytic agents. The SUCRA values are shown in Figure 4b, and the league table is shown in Figure 5b.

Pulmonary Artery Systolic Pressure

There were 8 studies [18-21, 25, 27, 36, 40] including 603 patients reporting the PASP. All the studies were two-arm studies, and the network evidence map is shown in Figure 3c. The weight of each study was shown in online supplementary Table 2. Alteplase reduced the treated PASP significantly compared to heparin, with a statistically significant difference (mean difference = −11.36, 95% CI, −21.45, −1.56). There was no statistically significant difference in the PASP after treatment when comparing different thrombolytic agents. The SUCRA values are shown in Figure 4c, and the league table is shown in Figure 5c.

Major Bleeding

There were 21 studies [17, 18, 21, 23, 27-32, 34-40, 42-45] including 2,567 patients reporting major bleeding. All the studies were two-arm studies, and the network evidence map is shown in Figure 3d. The weight of each study is shown in online supplementary Table 2. There was no significant difference in the incidence of major bleeding between different thrombolytic agents and heparin or between different thrombolytic agents. The SUCRA values are shown in Figure 4d, and the league table is shown in Figure 5d.

Minor Bleeding

There were 17 studies [17-19, 21, 23, 27-32, 37, 38, 42-45] including 2,327 patients reporting minor bleeding. All the studies were two-arm studies; the network evidence map is shown in Figure 3e. The weight of each study was shown in online supplementary Table 2. Compared with heparin, the incidence of minor bleeding associated with tenecteplase was higher than that with heparin, and the difference was statistically significant (RR = 3.27, 95% CI, 1.36, 7.39). Compared with different thrombolytic drugs, the incidence of minor bleeding associated with tenecteplase was higher than that with streptokinase, and the difference was statistically significant (RR = 3.22, 95% CI, 1.01, 11.10). The SUCRA values are shown in Figure 4e, and the league table is shown in Figure 5e.

Subgroup Analysis

We performed a subgroup analysis on different types of acute PE (massive and submassive PE). 6 studies (304 patients) [19, 30-33, 35] reported massive PE, and 14 studies (2,173 patients) [17, 18, 20-25, 27-29, 34, 37, 38] reported submassive PE. The results are shown in online supplementary Table 3. Based on the results of the subgroup analysis of acute PE, the sample size in each subgroup was too small, and there was a high risk of small sample bias.

Publication Bias Test

Comparison-adjusted funnel plots for different outcomes were plotted for publication bias tests, and the results showed poor symmetry, suggesting a possible degree of publication bias (online suppl. Fig. 4).

Discussion

Thrombolysis in patients with acute PE who present with hypotension is now widely accepted by most clinicians and society guidelines; however, it is mostly unnecessary in patients with acute PE who are hemodynamically stable and may be considered on an individual basis in isolated cases when the clinician assesses that the risk of benefit from thrombolysis outweighs the risk of bleeding, and after considering the patient’s values and wishes [7, 46]. Thrombolytic drugs directly activate plasminogen to form fibrinolytic enzymes, which degrade the fibrin clot and exert a thrombolytic effect. At present, the thrombolytic drugs currently in clinical use can be divided into three generations according to the sequence of discovery and drug characteristics. The first generation of thrombolytic drugs includes mainly urokinase and streptokinase, which can act directly on the endogenous fibrinolytic system, accelerate the cleavage of plasminogen to produce plasmin, accelerate the degradation of the fibrin clot and other substances, and thus play a thrombolytic role; the second generation of thrombolytic drugs includes mainly recombinant tissue-type plasminogen activator (rt-PA); third-generation thrombolytic drugs include reteplase and tenecteplase, which can act selectively on the surface of the thrombus and penetrate directly into the thrombus to accelerate thrombus dissolution [47]. Different thrombolytic drugs may have different thrombolytic effects due to their different mechanisms of action; it has not been determined which preparation or regimen works best. Clarifying the effect of different thrombolytic drugs on PE will largely influence their clinical application.

In this study, we compared the efficacy and safety of five thrombolytic agents for the treatment of acute PE among themselves and compared with anticoagulants using a network meta-analysis. The results of this network meta-analysis showed that thrombolytic therapy (except tenecteplase) was more effective than anticoagulant alone in patients with acute PE. This is basically similar to previous studies. A meta-analysis that included 15 RCTs comparing the efficacy of treatment in two groups of patients with acute PE using either anticoagulation alone or anticoagulation combined with thrombolysis found that the prognosis (including mortality and PE recurrence rate) of the anticoagulation combined with thrombolysis group was better than that of the anticoagulation alone group [9]. Another meta-analysis has also demonstrated that thrombolytic therapy was associated with reduced all-cause mortality and PE recurrent rate in the thrombolysis group compared with the anticoagulation group [8]. However, previous studies did not compare differences among different thrombolytic agents because they compared all thrombolytic agents as a whole with anticoagulants. In our study, we compared different thrombolytic agents in the effectiveness of thrombolysis in acute PE. Regarding the effectiveness of thrombolytic therapy, compared with anticoagulation alone, reteplase, alteplase, streptokinase, and urokinase can reduce patient mortality, but tenecteplase cannot reduce mortality; also, reteplase had lowest mortality rate among all thrombolytic agents according to SUCRA values, but there was no statistical difference. Compared with anticoagulants alone, alteplase not only reduced mortality but also reduced recurrence of PE and better improved the post-treatment profile of PASP; alteplase had the lowest recurrence rate of PE among all thrombolytic agents according to SUCRA value, but there was no statistical difference.

Although these cumulative results can generally be considered to represent the benefit of thrombolytic therapy, the risk of bleeding events remains an important restrictive issue for the use of thrombolytic agents in clinical practice. In a previous meta-analysis by Chatterjee et al. [8], it was found that initial thrombolytic therapy in patients with PE can increase the risk of massive hemorrhage compared with initial anticoagulant therapy. This was inconsistent with our findings. Our study found that for major bleeding incidence, there was no increase in major bleeding with different thrombolytic drugs compared to anticoagulation alone; for minor bleeding incidence, the risk of minor bleeding was significantly higher with tenecteplase than with streptokinase and heparin; also, among all thrombolytic agents, tenecteplase had the highest bleeding risk and streptokinase had the lowest bleeding risk as derived from the SUCRA values, but it was not statistically significant. The reason for the difference may be related to the inconsistency of the included literature and analysis methods. Bleeding during thrombolysis most often occurred at the site of invasive manipulation (such as arterial puncture) [48], so invasive manipulation should be minimized as much as possible when thrombolytic therapy is being performed. Bleeding at the puncture site of the blood vessel should be controlled by compression and bandage after manual compression.

It is also clinically important to differentiate between different types of PE. In this study, we performed subgroup analysis according to the different types of PE (massive PE and submassive PE). Overall, after our subgroup analysis, most of the results in the subgroups came from only one or two studies, and the sample size within each group became smaller; it is possible to draw “false negative conclusions” denying the effectiveness of the intervention or “false positive conclusions” affirming the effectiveness of the intervention. The results are therefore somewhat unsatisfactory and prone to bias. Only when the sample size of the subgroup is large enough can the conclusions obtained become more reliable. More studies are needed in the future to confirm the effectiveness and safety of different thrombolytic drugs for different types of PE.

Thrombolytic therapy may be beneficial for PE patients with a high risk of death and a low risk of bleeding, while when there is a low risk of death and a high risk of bleeding it may cause harm. Future studies should also address the concomitant use of other agents, particularly new oral anticoagulants and thrombolytic agents, in patients with PE [49]. Convenience, good efficacy, and low side effects are the goals of new drugs. These findings need to be confirmed by large-scale prospective studies.

Strength and Limitation

Our systematic assessment has several advantages. First, it provides the most comprehensive and reliable body of evidence to date. Second, we have considered multiple key outcomes related to the effectiveness of thrombolytic therapy in patients with PE.

There are several potential limitations to this study. First, despite the large number of patients included, the included studies were mainly short-term follow-ups and did not cover long-term outcome indicators such as chronic thromboembolic pulmonary hypertension. Therefore, the impact of these drugs on long-term outcomes of PE patients has not been discussed in our paper, and more long-term follow-up studies are needed. Second, the articles included a diversity of criteria and treatment regimens; our approach may not have captured the diversity of treatment regimens and definitions used. Third, we did not perform subgroup analyses for thrombolytic dose due to the small number of included articles.

Conclusion

In conclusion, for patients with acute PE, four thrombolytic agents (alteplase, reteplase, streptokinase, and urokinase) appeared to be superior in efficacy compared with anticoagulant alone due to a reduction in mortality and no increase in major and minor bleeding risk. Alteplase may be a better choice compared with anticoagulant alone because it not only reduced mortality but also reduced PE recurrence rate and treated PASP. Tenecteplase did not reduce mortality compared with anticoagulants alone and may not be a good choice of thrombolytic agents due to an increase in minor bleeding compared with streptokinase and anticoagulants alone. In the clinical treatment, thrombolytic drugs should be rationally selected to optimize the thrombolytic regimen and achieve as good a balance as possible between thrombolysis and bleeding. More large-scale prospective studies are needed to confirm the difference between different thrombolytic drugs.

Statement of Ethics

Ethical approval and consent were not required as this study was based on publicly available data.

Conflict of Interest Statement

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

Funding Sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions

Hong-Yan Li and Ying-Hui Jin designed this study and wrote the draft manuscript. Yong-Bo Wang and Xiang-Ying Ren analyzed the data. Jing Wang performed the literature search. Hai-Shan Wang reviewed discrepancies regarding the quality of the included studies and reviewed the manuscript.

Data Availability Statement

This document contains all data generated or analyzed during this study and its online supplementary material. Further inquiries can be directed to the corresponding author.

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