To our knowledge, the present study is the first, largest and most comprehensive meta-analysis of the efficacy and safety of tenecteplase in PE patients, summarizing multiple RCT and cohort studies. There are several key points from this meta-analysis and systematic review. First, for patients with high-risk PE, tenecteplase could improve patient survival over 30 days without increasing major bleeding rates. Second, for patients with intermediate-risk PE, tenecteplase could prevent the disease progression and improve the clinical symptoms rapidly, decreasing the length of ICU stay and cost. However, tenecteplase could increase the major bleeding risk in the short term as could other thrombolytic agents. Furthermore, tenecteplase has some unique advantages such as high fibrin specificity and convenient usage. In summary, we believe tenecteplase is a promising candidate for patients with intermediate/high risk PE, especially in the COVID-19 era.
As a third-generation thrombolytic agent, tenecteplase has been widely studied in thrombotic diseases due to its unique advantages. We summarized the advantages and disadvantages of the different thrombolytic agents in supplement Table 1. Urokinase and streptokinase are the first-generation thrombolytic agents, which over-degrade fibrinogen due to the low fibrin specificity, causing serious adverse effects such as major bleeding. Furthermore, streptokinase is an antigenic foreign bacterial protein, increasing the likelihood of anaphylactic reactivity.26 Alteplase, a second-generation thrombolytic agent, shows lower bleeding risk. In comparison, tenecteplase has more advantages. First of all, tenecteplase demonstrates the greatest fibrin specificity, decreasing the risk of major bleeding. Secondly, the clearance of tenecteplase is approximately eight-fold slower than alteplase. In contrast, alteplase requires a continuous intravenous infusion for 2 hours while tenecteplase is administered in 5-10 minutes by a single bolus.10,27 In current clinical practice, it is imperative to reduce contact with patients suspected of COVID-19, given the severity of the current pandemic. Due to its all-at-once convenient administration, tenecteplase can decrease the exposure time of healthcare providers to the virus.
Moreover, tenecteplase has been under research in other thrombotic studies such as acute myocardial infarction (AMI) and acute ischemic stroke (AIS) (Table 4 and 5). In 2000, tenecteplase has been approved to treat AMI by the Food and Drug Administration (FDA), as it reduces the risk of major bleeding with the similar efficacy compared to alteplase.11 Although tenecteplase has not yet received FDA approval for AIS, a meta-analysis found tenecteplase was noninferior to alteplase and improved the neurologic function in the early stage.28 Also, tenecteplase may reduce the delay in endovascular thrombectomy and may be more suitable for large vessel occlusions because of convenient usage.28 These studies provide a basis and demonstrate the potential for tenecteplase in PE studies.
Table 4
Tenecteplase therapy in patients with thrombotic diseases.
| Time of FDA approval | Advantages | Disadvantages |
AMI | 2000 | ¬ Similar efficacy with alteplase in reperfusion therapy ¬ Reducing the risk of major bleeding | ¬ 30-day mortality was similar in patients receiving alteplase |
AIS | Not approved | ¬ Higher rates of both recanalization and early neurological improvement ¬ Not increasing intracerebral bleeding or mortality ¬ Noninferior to alteplase in treatment | ¬ All-at-once administration and longer serum half-life may allow hemostasis to return more quickly |
APE | Not approved | ¬ Similar efficacy and safety as streptokinase, heparin and alteplase ¬ May decrease duration of stay in the ICU ¬ May have higher rates of improvement in clinical symptoms and SaO2 | ¬ Increases the risk of major bleeding over anticoagulation for intermediate-risk APE |
Notes: AMI, acute myocardial infarction; AIS, acute ischemic stroke; APE, acute pulmonary embolism; FDA, Food and Drug Administration; ICU, intensive care unit; SaO2, blood oxygen saturation |
Table 5
The meta-analyses of tenecteplase in patients with thrombotic diseases.
Disease type | Author, year [Refs.] | Number of studies included | Main findings |
AMI | Guillermin et al. (2016) [10] | 4 | Tenecteplase reduces the risk of major bleeding with the similar efficacy as alteplase in the treatment of AMI. |
AIS | Burgos et al. (2019) [27] | 5 | Tenecteplase is noninferior to alteplase in the treatment of AIS. |
APE | Our study (2021) | 6 | Tenecteplase is recommended for patients with intermediate/high-risk APE. |
Notes: AMI, acute myocardial infarction; AIS, acute ischemic stroke; APE, acute pulmonary embolism. |
Despite the lack of prospective studies of tenecteplase in patients with high-risk PE, limited evidence supports the use of this drug. The 2019 ESC/ERS guideline recommended systemic thrombolytic therapy for patients with high-risk PE5. A large prospective cohort study concluded that thrombolysis during cardiopulmonary resuscitation was associated with higher 30-day survival rate without increasing the rate of hemorrhage in high-risk PE patients, whether the thrombolytic agent was tenecteplase or alteplase21. Therefore, we believed that tenecteplase can benefit patients with high-risk PE in efficacy and safety aspects.
The current evidence included studies that mainly focused on intermediate-risk PE group. For these normotensive PE patients, tenecteplase reduced the risk of hemodynamic failure24, which indicated that tenecteplase prevented the disease progression. Additionally, tenecteplase was better than UFH at reducing RVD in the early stage20 but did not affect short/long-term mortality. Compared with streptokinase, studies have found that tenecteplase could improve the clinical symptoms rapidly and enable patients to obtain better self-assessment of overall health function, especially for those with comorbid conditions such as recurrent venous thromboembolism or heart failure, which was also verified by Stewart et al and Agrawal et al.22,25,29,30,31 Similarly, an observational study found that tenecteplase could reduce heart rate, increase the systolic blood pressure and oxygen saturation.29 Furthermore,tenecteplase could decrease the dependency for ICU and the length of stay, therefore, the application of tenecteplase may reduce the cost of therapy22,25.
However, current results on the risk of bleeding with tenecteplase are controversial. Clinicians are cautious about thrombolytic therapy mainly because of the concerns of bleeding. Becattini et al20 found that tenecteplase did not increase excessive major bleeding rates. While Meyer et al24 believed that teneteplase may increase the risk of major bleeding, including intracranial hemorrhage, within 7 days[90(17.8%) vs 18(3.6%), p<0.001)]. According to our meta-analysis, we found tenecteplase was associated with higher bleeding risk in 7 days for intermediate-risk PE patients and did not affect long-term bleeding events. As the guideline indicated, we believed tenecteplase, similar to other thrombolytic agents, may increase the risk of bleeding for aged patients who have more comorbidities5. However, some retrospective studies showed that tenecteplase did not increase, but reduced the hemorrhagic rates25,31. Moreover, Figure 5 indicates that tenecteplase may be weakly related to risk of major bleeding. Therefore, we speculated that the elevated bleeding risk in some studies was associated with drug doses, numbers of patients enrolled, and different characteristics of the patients. The current doses of tenecteplase were 0.5 mg/kg in most studies involved, with a 5mg step-up for every 10 kg increase from 60 to 90 kg; however, the 0.25 mg/kg dose of tenecteplase was found to be associated with early neurological improvement and reduced tendency of intracranial hemorrhage compared to other thrombolytic agents in the treatment of stroke.32 Our previous study on thrombolysis also showed that half-dose thrombolysis reduced the risk of bleeding with similar efficacy. 33 Additionally, applying catheter-directed thrombolysis with tenecteplase to treat PE patients with RVD appeared to improve right ventricle function without increasing bleeding risk34. Recently, the HI-PEITHO study launched and started enrollment, which aims to assess whether ultrasound-facilitated, catheter-directed thrombolysis and standard anticoagulation are associated with adverse outcomes for patients with intermediate-high risk PE.35 Therefore, catheter-guided administration of low-dose teneteplase may benefit patients with intermediate-risk PE. Moreover, tentecteplase is advantageous owing to its convenient administration, minimizing the exposure of healthcare providers to infection in the COVID-19 pandemic. In conclude, we believed further studies would be necessary to validate the efficacy and safety of tenecteplase at a lower dose or the different methods of administration in intermediate-risk PE patients.
We believed high-risk PE patients are suitable for tenecteplase, however, for patients with intermediate-risk PE, it was not appropriate to apply tenecteplase with the same dose or regimen as with high-risk PE patients. Studies have reported that normotensive PE patients with elevated troponin and BNP, or lactate≥ 2 mmol/L were at a higher risk of the adverse outcomes, and indicated a potential need for more aggressive systemic thrombolytic treatment instead of anticoagulants alone in these patients.36 In this way, these patients should be closely monitored, and teneteplase could be beneficial when hemodynamic instability occurs.
We acknowledge some limitations of our analysis. First, a publication bias is possible, however, as the number of studies included was limited, no filled funnel plot for publication bias or Egger’s test was generated or performed. Second, the sample sizes of some subgroups were too small to assess heterogeneity between studies and draw an accurate conclusion. Third, the PE risk level was not available for all involved studies, which may lead to misclassification.