This study compared half-dose alteplase and low molecular weight heparin (LMWH) as initial treatment options in patients with intermediate-high risk PE. Although one-month and one-year mortality rates were lower in the thrombolytic group, the differences were not statistically significant. To our knowledge, this is the first real-life study comparing these two agents in this specific risk group. No significant differences were observed between the groups regarding major bleeding, minor bleeding, or long-term complications. The multivariate analysis demonstrated that advanced age and increased heart rate on the second day were independently associated with one-month mortality, while thrombolytic therapy, gender, and second-day PaO2/FiO2 ratio were not found to be as risk factor.

Intermediate-high risk PE is associated with greater mortality than intermediate-low-risk PE. While the ESC/ERS guidelines recommend anticoagulation and close monitoring for these patients, fibrinolytic therapy is suggested only in cases of hemodynamic deterioration. Similarly, the American Society of Hematology advises against routine thrombolytic use in hemodynamically stable patients with right heart strain. This cautious approach is primarily due to insufficient supporting evidence [2, 11]. On the other hand, the use of thrombolytics for intermediate-high risk PE patients is often discussed by “Pulmonary Embolism Response Teams” [12, 13]. In our clinical practice, patients in this group are treated with half-dose thrombolytic therapy after the establishment of EGEPET unless contraindicated.

Mirambeaux et al. followed 1015 hemodynamically stable patients prospectively. According to their results, intermediate-high risk PE was found in 97 (9.6%) of the patients based on the ESC/ERS PE guideline, and The one-month all-cause mortality was 24% in this group [14]. The mortality rate is important and too high to be ignored. In our presented study, the mortality rate was 6,7% in the thrombolytic group and 15,8% in the anticoagulation group. However, the contribution of the reperfusion therapy to low mortality rate in our series is not sufficient to suggest because of the limited number of patients.

Arterial hypotension, tachycardia, low partial oxygen pressure, and low oxygen saturation parameters are seen as risk factors for short-term (30-day) mortality, and in addition to hemodynamic instability [15, 16]. Declined BP and PaO2/FiO2 ratio, and increased pulse value are accepted as poor prognosis signs during follow-up. In our study, vital signs of patients were similar in both groups on admission; but after half-dose thrombolytic treatment, dramatic improvement was seen in pulse rate and in PaO2/FiO2 value. These results point to clinically rapid improvement in the thrombolytic group. The observed improvements in vital signs—specifically, the significant enhancements in PaO₂/FiO₂ ratios and reductions in pulse rates—suggest a rapid physiological response to half-dose thrombolytic therapy. These findings may indicate early reversal of right ventricular dysfunction and improved pulmonary perfusion, which are critical in the management of intermediate-high risk PE patients. Although the improvement in PaO₂/FiO₂ ratio suggests enhanced oxygenation following thrombolysis, this marker should be interpreted with caution, as it may not directly point clinical endpoints such as mortality or recurrence. In recent years, that patients in this PE classification are closely followed up because of disease severity and thrombolytic therapy. Therefore, the longer ICU day observed in the thrombolytic group may reflect differences in treatment approach and raised awareness of clinical severity.

Both thrombolytic therapy and anticoagulation therapy have well-recognized complications. Meta-analysis made by Zuo et al. has shown that thrombolysis increases major bleeding by 2.84 times and minor bleeding by 2.97 times compared to the anticoagulation [17]. Although thrombolytic therapy increases the risk of bleeding, it corrects signs of right ventricle failure, rapidly and effectively [4]. In this situation, the decision to use thrombolytic therapy becomes an important and difficult clinical problem. And that should be remembered the characteristics of the patient group in studies is important for evaluating results.

Riera-Mestre et al. analyzed the efficacy and side-effects of the thrombolytic therapy in their meta-analysis composed of eleven studies. Different thrombolytic agents were assessed in here research results showed that thrombolysis did not reduce mortality risk, but increased bleeding risk. With these results, the authors do not recommend the use of thrombolytics in intermediate-risk PE [18]. In this meta-analysis, the patients were not classified as intermediate-high and intermediate-low risk according to new guidelines. However, there are also other studies reporting that thrombolytic therapy does not increase the risk of bleeding compared to anticoagulation therapy. [19]. In the presented study, no major bleeding was observed, and no difference was found between the anticoagulant (5.3%) and thrombolytic (8.5%) groups in terms of minor bleeding.

Meyer et al. compared tenecteplase (30–50 mg) with unfractionated heparin in PE patients with right ventricular failure and elevated troponin. The primary endpoint was hemodynamic decompensation within 7 days, which occurred less frequently in the thrombolytic group (2.6% vs. 5.6%, statistically significant). However, this difference was not significant in patients younger than 75 years. Major bleeding events were more common in the thrombolytic group. The 30-day mortality rates were 2.4% and 3.2% in the thrombolytic and anticoagulation groups, respectively, without a significant difference. Although case definitions were similar, patients with hemodynamic decompensation during follow-up and those receiving full-dose thrombolysis were excluded from our study. Additionally, different thrombolytic agents were used [4].

The MOPETT study compared the efficacy of thrombolytic therapy with low-dose tissue plasminogen activator and anticoagulant in patients with intermediate-risk. Heparin infusion or enoxaparin was administered for anticoagulation therapy. In MOPETT trial, intermediate risk PE was defined as clinical findings of PE and the presence of severe radiological PE. The hospital mortality rate was 1.6% in the thrombolytic group and 5% in the anticoagulation group. While no recurrent embolism occurred in the thrombolytic arm, 5% of the anticoagulation arm had recurrent embolism (p = 0.08). No bleeding was observed in both groups. The hospital mortality rate in our study and the frequency of recurrent emboli were higher compared to MOPETT study. Recurrent embolism rate in both studies was lower in the thrombolytic arm than the anticoagulation arm. In the MOPETT study, right ventricle failure and troponin positivity were not assessed, the patients were classed into only radiological findings rather than clinical severity. [20]. Moreover, our patient group was older than MOPETT trial group and was evaluated with Charlson comorbidity index. In MOPETT, while there was no difference between the groups in terms of the presence of one-to-one comorbidity, the burden of all comorbidities did not seem to be evaluated.

In Türkiye, Yılmaz et al. compared the efficacy of LMWH and 50 mg alteplase in patients with PE who were hemodynamically stable but had right ventricle failure findings in CTPA or ECHO. There were 38 patients in each group. One death (3%) occurred in the thrombolytic group within 30 days, while death was observed in 4 (10%) patients in the anticoagulation group (p = 0.36). Additionally, hemodynamic decompensation/death was observed in 1 patient in the thrombolytic group and in 10 patients in the anticoagulation group (p = 0.009). In other words, one-month mortality was not affected by half-dose alteplase, but the development of hemodynamic decompensation could be prevented. Although similar in design to our study, biomarkers were not used in this study as indicators of cardiac damage [6].

Guru PK et al. investigated ultra-low-dose systemic tPA (25 mg) in 4 patients with high risk submassive PE and found that even significantly reduced doses could yield clinical benefit without markedly increasing the bleeding risk [21]. Their focus was primarily ultra-low dose tPA application. Krishnan AM et al. compared catheter-directed thrombolysis with systemic thrombolysis and anticoagulation alone in patients with acute PE and cor pulmonale. They noted better hemodynamic recovery and RV function improvement in the thrombolysis group [22]. These findings indicate that alternative treatments strategies and different dosing may be considered for this patient population in the future.

Findings of RV failure and large thrombus in the pulmonary arteries increase the risk of CTEPH [23]. The results of the study following 219 patients with intermediate risk PE presented that 13.2% of patients develop right ventricular dysfunction on ECHO after CTEPH status or post-PE impairment [24]. Although thrombolytic therapy is thought to be protective against CPTE or CTEPH, more data is needed on this subject. When the MOPETT study was analyzed in terms of the development of pulmonary hypertension (systolic pulmonary artery pressure above 40 mmHg on ECHO), the rate of development of pulmonary hypertension during follow-up was 57% in the group receiving anticoagulation and 16% in the group receiving thrombolytics (p < 0.001) [20]. In the present study, the rates of CPTE or CTEPH were the same between the two groups, but it should be remembered that the follow-up period was longer in patients receiving anticoagulants.

Limitations:

This single-center study, investigating half-dose alteplase efficacy, has limitations. First, its single-center, real-life observational design limits generalizability and may make it prone to observer bias. Second, the thrombolytic cases were prospectively followed; but anticoagulant group data were collected retrospectively as a historical control group. The observed improvements in the thrombolytic group should be interpreted with caution, as the use of a historical control group may have introduced selection and documentation bias, potentially reflecting advances in multidisciplinary evaluation (EGEPET) and supportive care over time rather than the intervention itself. It should also be noted that the observed improvements may partially reflect the impact of systematic, team-based management introduced with the establishment of EGEPET. Third, the targeted sample size was not reached, with only 97 patients over seven years due to the rarity of this group. The study may be underpowered to detect statistically significant differences in outcomes such as mortality, and several p-values approaching significance raise the possibility of a type II error. Fourth, in the multivariable analysis, the confidence intervals of the parameters found to be statistically significant were detected as widely. They should be evaluated carefully. Fifth, it was not a randomized controlled trial, but baseline demographics and clinical findings were comparable. Sixth, patients requiring dose escalation or with deteriorating hemodynamics were excluded. Lastly, follow-up during the COVID-19 pandemic (2020–2021) was challenging. Despite these limitations, this study reflects real-life clinical practice.