Pulmonary embolism (PE) is the third leading cause of cardiovascular mortality worldwide. Current guidelines recommend early reperfusion for high-risk and intermediate-high-risk PE, yet systemic thrombolysis and percutaneous therapies are frequently underutilized, and no specific timing for reperfusion is defined, unlike in acute myocardial infarction or ischemic stroke. As most PE-related in-hospital deaths occur within the first hours and thrombus composition changes over time, defining an optimal reperfusion time window may improve survival and prevent hemodynamic deterioration. We therefore propose a national, multicenter, prospective observational study to evaluate the prognostic impact of reperfusion timing, using systemic thrombolysis or catheter-directed therapies, on in-hospital mortality and haemorrhagic or cardiovascular complications.

Pulmonary embolism (PE) is currently the third leading cause of cardiovascular mortality worldwide. According to international guidelines, patients who are hemodynamically unstable at presentation (classified as high-risk according to the current European Society of Cardiology classification) and those at intermediate-high risk-defined as patients who are hemodynamically stable at admission but present with right ventricular dysfunction and positive cardiac ischemia biomarkers and subsequently develop sudden hemodynamic deterioration, should undergo reperfusion as early as possible.

At present, reperfusion in these patients is mainly achieved through systemic thrombolysis or percutaneous treatments. However, these strategies are frequently underutilized because of patients' comorbidities and bleeding risk. Notably, current international guidelines do not define a specific time window within which reperfusion should be performed using either approach, in contrast to what is well established in guidelines for acute myocardial infarction and ischemic stroke.

Given that most in-hospital deaths related to PE occur within the first hours after symptom onset and hospital admission, and considering that the histological composition of thrombi undergoes time-dependent changes that may partially reduce the effectiveness of reperfusion therapies, identifying a temporal cutoff within which reperfusion confers maximal clinical benefit would be highly relevant. Such a cutoff could improve both patient survival and the prevention of hemodynamic deterioration when performing systemic or percutaneous reperfusion.

To address this knowledge gap, we propose a national, multicenter, prospective observational study that could also could serve as a platform for registry-based randomized clinical trials. The primary aim of the study is to identify optimal management strategies for patients with intermediate-high-risk or high-risk PE, with a particular focus on the most appropriate timing of systemic reperfusion or catheter-directed therapies (CDTs), when indicated, and to evaluate their prognostic impact. Specifically, the study will assess the relationship between reperfusion timing (systemic thrombolysis or CDTs) and in-hospital mortality. Additionally, the association between different reperfusion time windows and the occurrence of haemorrhagic or cardiovascular complications will be evaluated.

Inclusion Criteria:

• Age ≥ 18 years
• Patients with a diagnosis of intermediate-high or high pulmonary embolism confirmed by computed tomography pulmonary angiography (CTPA), pulmonary angiography, or echocardiography (evidence of a floating thrombus in the right atrium or right ventricle, or proximal visualization of thrombus in the pulmonary artery).
• Classified as high-risk or intermediate-high-risk according to the 2019 European Society of Cardiology guidelines.
• Provision of informed consent for the processing of personal data.

Exclusion Criteria:

• Age < 18 years
• Patients in whom a diagnosis of acute high-risk or intermediate-high-risk pulmonary embolism has been excluded.
• Inability to provide informed consent.

Patients with a confirmed diagnosis of high-risk or intermediate-high-risk pulmonary embolism according to the 2019 European Society of Cardiology guidelines.