Chronic Thromboembolic Pulmonary Hypertension Incidence, Post-pulmonary Embolism Syndrome and Possible Role of Transcatheter Therapy in Prevention

Abstract

Pulmonary embolism (PE) presents both acute and chronic complications that significantly affect patient outcomes. Acute complications include syncope or sudden death, often resulting from severe hypoxaemia or right ventricular failure; and early recurrence of the embolic event. Chronic complications, which can develop over time, are often grouped under post-embolic syndrome (PES), a condition affecting more than half of PE survivors. Symptoms of PES include persistent dyspnoea and reduced exercise tolerance. PES is associated with several serious conditions, such as chronic thromboembolic pulmonary hypertension, chronic thromboembolic pulmonary disease, right ventricular dysfunction, physical deconditioning, and psychological harm. Although promising catheter-directed therapies are under investigation for acute PE treatment, their effectiveness in preventing chronic complications has yet to be confirmed by large-scale randomised controlled trials.

Pulmonary embolism (PE) refers to the obstruction of the pulmonary circulation caused by a preformed thrombus in the venous vascular territory. It presents with a wide variety of features. Although some of its most common presentations are non-specific, such as dyspnoea, cough, pleuritic pain, tachycardia or tachypnoea, its more severe forms can also manifest as cardiogenic shock or sudden death.1

The current annual incidence of PE is estimated to range between 39 and 115 cases per 10,000 inhabitants, a figure that has progressively increased since the introduction of D-dimer and pulmonary artery CT angiography (CTA) as diagnostic tools in the 1990s.2,3 The mortality attributable to this condition in Europe is approximately 300,000 cases per year, with the majority of cases developing during hospitalisation.4

Syncope, death (which usually occurs due to hypoxaemia, right ventricular failure or a combination of both) and early recurrence of embolism are acute complications of this condition. In its chronic course, complications would include late recurrence of embolism and post-embolic syndrome (PES).5 PES encompasses a wide range of conditions characterised by the persistence of symptoms related to a prior embolic event (mainly dyspnoea and limited exercise capacity), despite adequate anticoagulant treatment for ≥3 months. More than half of patients with a history of PE will experience some form of PES, with chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic pulmonary disease (CTEPD) being its most prominent manifestations. Rightventricular dysfunction (RVD) and functional impairment are also included in this term, with physical deconditioning and deterioration of mental health being responsible for the latter.6,7 Figure 1 shows the different components of PES.

Figure 1: Components of Post-embolic Syndrome.

CO = cardiac output; mPAP = mean pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure.

Just as there is an established role for interventional techniques in specific scenarios related to acute PE with the primary goal of preventing death, the usefulness of these therapies in the prevention of PES is not yet clarified. This review also aims to present the available evidence in this regard.

Post-embolic Syndrome

Chronic Thromboembolic Pulmonary Hypertension

CTEPH is a type of pulmonary hypertension (PH) caused by unresolved thrombi that form fibrotic structures, obstructing the pulmonary vascular tree and causing microvascular alterations. These changes are associated with pre-capillary PH, haemodynamically confirmed by the following criteria: mean pulmonary artery pressure (mPAP) >20 mmHg, pulmonary vascular resistance (PVR) >2 Wood units, and pulmonary capillary wedge pressure (PCWP) ≤15 mmHg. After an acute embolism, to diagnose CTEPH, these characteristics must be present after at least 3 months of effective anticoagulation since the index event.8

Interestingly, only approximately 3% of patients with PE will develop CTEPH as a sequela.9 In contrast, of the patients diagnosed with CTEPH, 75% have an identified history of acute PE.10 From this we can conclude that, in addition to embolic events (which may or may not go unnoticed), other factors must coexist that lead to the chronicity of thrombi, something that typically does not occur in patients with PE.11

Although CTEPH is less common than other PES manifestations, such as recurrent PE (2–8% annually) or chronic pulmonary impairment (affecting 20–50% of survivors), its severe impact on quality of life and treatment options makes early recognition and intervention essential. These data emphasise the importance of vigilant monitoring and long-term follow-up in PE survivors to improve outcomes and optimise resource use.6,7

Some of the identified risk factors significantly associated with the development of CTEPH are listed in Table 1. No association has been found between CTEPH and the mutations characteristic of pulmonary arterial hypertension.8,12

Table 1: Risk Factors Significantly Associated with Chronic Thromboembolic Pulmonary Hypertension8.

Related to the Patient
Non-O blood group Previous splenectomy History of infected ventriculo-atrial shunts for the treatment of hydrocephalus Indwelling catheters and leads Thyroid replacement therapy Cancer Chronic inflammatory disorders Elevated levels of factor VIII and von Willebrand factor.
Related to the Pulmonary Embolism Episode
Previous episodes of pulmonary embolism or deep vein thrombosis Large burden of thrombi at initial diagnosis of pulmonary embolism Submassive embolism Chronicity data in the CT scan Right ventricular dysfunction

Diagnosis should be suspected in patients with persistent symptoms after the event, those with RVD at the time of diagnosis or those with risk factors for CTEPH. If any of these criteria are present, an echocardiogram should be performed, and if the probability of pulmonary hypertension is high (Table 2 ), right heart catheterisation (RHC) should be undertaken.13

Table 2: High-probability Indicators of Pulmonary Hypertension.

High-probability Indicators

Echocardiographic Signs

Peak tricuspid regurgitation velocity >3.4 m/s Or Peak tricuspid regurgitation velocity 2.9–3.4 m/s + 2 or more echocardiography PH signs

Ventricles RV/LV basal diameter/area ratio >1 Flattening of the interventricular septum (eccentricity index >1.1 in systole and/or diastole) TAPSE/sPAP ratio <0.55 mm/mmHg Pulmonary artery RVOT AT <105 ms and/or mid-systolic notching Early diastolic pulmonary regurgitation velocity >2.2 m/s PA diameter >AR diameter PA diameter >25 mm Inferior vena cava and right atrium RA area (end-systole) >18 cm2 IVC diameter >21 mm with decreased inspiratory collapse (<50% with a sniff or <20% with quiet inspiration)

AR = aortic root; AT = acceleration time; IVC = inferior vena cava; LV = left ventricle; PA = pulmonary artery; PH = pulmonary hypertension; RA = right atrium; RV = right ventricle; RVOT = right ventricular outflow tract; sPAP = systolic pulmonary artery pressure; TAPSE = tricuspid annular plane systolic excursion.

Aside from haemodynamics, the most useful tools are ventilation/ perfusion scintigraphy and pulmonary artery CTA. Specifically, scintigraphy is preferred as the first approach due to its higher sensitivity to detect perfusion defects, which is close to 100%. While CTA has comparable sensitivity for the detection of thrombi in lobar arteries, its accuracy drops to 86% when evaluating segmental arteries, as described in some series.14 However, it is crucial for confirming and characterising the thrombotic material and its relationship with vascular anatomy. Pulmonary angiography, although the gold standard, is now reserved for cases of suspected thrombotic burden exceeding CTA findings due to its invasiveness.13,14 Ring-like stenosis, pouches, webs, occlusions, and the extension of small vessel lesions are the most characteristic findings of this entity, and they should be accurately described given that they hold postoperative prognostic value and guide the invasive road map.5

From a treatment perspective, CTEPH is the only type of PH that is potentially curable through interventional procedures. The two available techniques for its treatment are pulmonary thromboendarterectomy (PEA) and balloon pulmonary angioplasty (BPA). PEA is the treatment of choice in cases of predominantly central involvement. In contrast, BPA is more suitable in cases of peripheral involvement, as a rescue therapy when the results of endarterectomy are suboptimal, or as an alternative for patients who would be candidates for surgical intervention but are deemed inoperable for other reasons. Pharmacological treatment in CTEPH is secondary, used mainly for pre-intervention preparation, management of residual PH, or as palliative care for inoperable patients.14

Chronic Thromboembolic Pulmonary Disease

Patients with perfusion defects or residual thrombus after 3 months of anticoagulation, dyspnoea on effort, and exercise-induced PH without resting PH are classified as having CTEPD.12

Although its significance remains uncertain, the persistence of vascular obstruction after the index PE event is as high as 50% on lung scintigraphy, much higher than the reported incidence of CTEPH.15 The pathophysiology of both processes, although not yet fully understood, is likely to be the same and involves a propensity for thrombi to become chronic despite anticoagulant treatment. Given that there is no linear relationship between thrombotic burden and haemodynamic impairment at follow-up, it is possible that the difference between the two processes lies in the degree of vascular reactivity to the disruption caused by thrombotic obstruction.16 Although these patients do not exhibit signs of PH at rest (and the echocardiogram is usually normal), they have symptoms during physical exertion that are disproportionate to their haemodynamic status, similar to those seen in patients with diagnosed CTEPH. The presence of ventilatory inefficiency and maladaptation of the right ventricle (RV) to physical exertion has been highlighted in patients with CTEPD who undergo cardiopulmonary exercise testing (CPET).17 These alterations are due, at least partially, to exercise-induced PH.18 The diagnosis of CTEPD is established with an mPAP/cardiac output slope between rest and peak exercise of >3 mmHg/l/min (demonstrated on exercise RHC), while mPCWP/cardiac output slope remains <2 mmHg/l/min, with no alternative diagnosis explaining these findings. However, other conditions (some of which occur in PES) frequently coexist, complicating the differential diagnosis.19

In this context, exercise catheterisation is a quickly evolving tool that is expected to deepen our understanding of this phenomenon and other conditions believed to stem from exercise-induced haemodynamic changes.20

CTEPD is less well-defined than CTEPH; and similarly, its treatment needs to be established. However, positive outcomes have been reported in terms of symptom improvement, quality of life, and functional class in symptomatic patients who have undergone PEA.21 Similarly, encouraging results have been published for patients treated with BPA, particularly regarding parameters less dependent on haemodynamics, such as the need for supplemental oxygen therapy.22

Right Ventricular Dysfunction

The sudden increase in pressure on the RV, resulting in RV dilation, ischaemia and inflammation, makes RVD a common finding during the acute phase of high- and intermediate–high-risk PE.23 However, the persistence of RVD during follow-up has not been extensively studied in the past, partly due to the challenge of achieving a consensus definition. A recent meta-analysis investigating the persistence of RVD (as reported by the included studies) following an acute PE identified a prevalence of 34% at 3 months for normotensive events, decreasing to 22% at 6 months in the same risk group. These figures are notably higher than the previously reported rate of 18% at 6 months.24 The search for an organic explanation for this phenomenon has also scarcely been pursued, and although studies such as the PEITHO-2 trial have attempted to identify risk factors, their results have been inconclusive thus far.25 Up to now, a clear correlation has been observed between the persistence of RVD during follow-up after PE and an increased incidence of CTEPH and CTEPD. However, although the presence of RVD during the acute phase is associated with worse 30-day outcomes, the significance of this correlation for long-term prognosis in asymptomatic patients remains an area for future research.24,26

Functional Impairment

As previously highlighted in major investigations such as the FOCUS study, the effects of a prior PE on quality of life extend beyond the scope of CTEPH and RVD, with a stronger emphasis on patient-reported symptoms rather than what is detected on imaging tests.27 Functional impairment following PE is the most common cause of PES. The underlying mechanism is thought to involve reduced physical activity due to dyspnoea after acute PE, which leads to deconditioning and exercise limitations, further exacerbating the deconditioning process. In addition, factors such as depressive disorder, fear of complications or recurrence, and post-thrombotic panic syndrome also contribute to physical inactivity, along with diminished engagement in both professional and social activities. Therefore, functional impairment following PE can be categorised into two primary components: the psychological impact and the resulting physical deconditioning. Ventilatory inefficiency is also a well-defined factor that limits functionality, and its prevalence is high in this group of patients (Figure 1 ).7

Psychological Impact

The majority of the literature on PE and its consequences has primarily focused on its organic implications. Nevertheless, the psychological impact of PE is significant, with its main manifestations including post-traumatic stress disorder, anxiety and depressive disorders. None of the questionnaires used to assess the quality of life in this context has been proven superior to others. However, most agree that there is a negative psychological effect after a PE event, which tends to lessen over time.28 Fear of recurrence, fear of dying during a future episode, and fear of potential health limitations are among the primary concerns and are particularly prevalent in younger patients.29 The incidence of anxiety and depression is difficult to define due to the lack of strict diagnostic criteria. Still, a significant correlation has been demonstrated between a history of PE and higher scores for both conditions compared with controls.30 An incidence of 3% for post-traumatic stress disorder related to previous PE has been reported, and the term ‘post-thrombotic panic syndrome’ has even been coined to describe this specific condition.31 Although depressive disorders, fear of complications or recurrence and post-thrombotic panic syndrome further contribute to physical inactivity and impairment in both professional and social activities, there appears to be a positive relationship between a more extended disease-free period and perceived quality of life, suggesting the possibility of improving the psychological aspects of PES through early intervention.7,28

Deconditioning

Deconditioning refers to a multifaceted process of physiological changes that arise from extended inactivity, prolonged bed rest or a sedentary lifestyle. This condition leads to a decline in key functional areas, including cognitive abilities and the capacity to carry out daily activities.32 In relation to PE, Kahn et al. conducted a series of CPET and imaging studies on 100 patients following their first PE episode, finding that nearly half had reduced VO₂ peak after 1 year.33 Almost all patients with decreased VO₂ also had exercise limitations consistent with deconditioning, with none showing circulatory limitations to exercise. Notably, 60% of those with exercise limitations had normal perfusion scans. Another smaller study of patients with submassive or massive PE similarly found deconditioning without signs of pulmonary vascular disease despite half showing abnormal RV function on echocardiograms.34 While neither study consistently performed RHC to definitively rule out pulmonary vascular disease, the absence of significant findings on CPET suggests that major pulmonary vascular disease is unlikely. Moreover, both studies found no correlation between residual obstruction on perfusion imaging or RV dysfunction on echocardiograms and reduced exercise capacity, further supporting the idea that deconditioning may be the primary cause of symptoms.35 Deconditioning, alone or with comorbidities, often causes functional decline after PE. Given that extended periods of inactivity are a key trigger for deconditioning, treatments aimed at accelerating recovery could have a significant positive effect on its prevention. Contrary to earlier beliefs, early mobilisation strategies are now widely recognised as effective preventive and therapeutic measures.36 However, targeting the underlying cause, that is, PE, through systemic or localised interventions may be a promising approach to prevent this entity. Further research in this area is encouraged.

Ventilatory Inefficiency

Ventilatory inefficiency is a potential cause of functional impairment and can be assessed non-invasively through CPET, primarily by evaluating the relationship between ventilation (VE) and carbon dioxide production (VCO₂). An elevated ratio of these two parameters often indicates a ventilation–perfusion mismatch, typically involving the vascular component. The VE/VCO₂ ratio is commonly increased in the presence of PH and is frequently impaired after PE.37 A 2020 study reported that although cardiopulmonary function did not fully recover after 6 months of anticoagulation following a PE, exercise capacity improved significantly and there was a gradual improvement in ventilatory efficiency.38 This finding suggests a potential need for longer durations of anticoagulant therapy in these patients.38

Role of Transcatheter Therapy in Preventing Post-embolic Syndrome

Reducing thrombotic load after PE may lower chronic complications. This, along with new large-calibre devices, has increased the use of catheter-directed therapies, often beyond guideline recommendations. This section will review whether percutaneous reperfusion therapy has been shown to improve long-term outcomes and decrease the occurrence of new embolic events and the development of PES after acute PE. The evidence available to date with the different techniques is summarised in Table 3.

Table 3: Clinical Trials on Medium- and Long-term Outcomes of Reperfusion Therapies in Pulmonary Embolism.

Therapy	Trial	Sample Size	Key Results
Systemic fibrinolysis	PEITHO39 (thrombolysis versus AC)	709 patients (359 tenecteplase and 350 AC)	CTEPH rates at 3-year follow-up: 2.1% versus 3.2% (p=0.79). No significant differences in RVD, functional limitations or reduction in residual dyspnoea.
	Kline et al.40 (Tenecteplase versus AC)	83 patients (40 tenecteplase and 43 AC)	No difference in the frequency of right ventricular dilation or hypokinesis at 90-day follow-up.
Catheter-directed thrombolysis	CANARY41 (CDT versus AC)	94 patients (48 CDT and 46 AC)	CDT patients showed reduction in RV/LV ratio by echocardiography at 72 h, with no differences in the proportion of patients with an RV/LV ratio >0.9 at 3 months.
Ultrasound-assisted thrombolysis	ULTIMA42 (USAT versus AC)	59 patients (30 USAT and 29 AC)	Significant reduction in the RV/RA gradient with USAT within 24 h but no significant differences in RV/RA gradient or the RV/LV ratio at 90 days.
	Avgerinos et al.43 (USAT versus AC)	128 patients (64 USAT and 64 AC)	No differences in RV/LV ratio, RVD, mean RVSP or the presence of dyspnoea related to the initial PE event at 1-year follow-up.
	SUNSET sPE44 (USAT versus AC)	72 patients (53 USAT and 19 AC)	6MWD and quality-of-life scores were comparable between the two groups at 3-month follow-up.
	KNOCOUT PE45 (no control group)	489 patients	At 3 months, improvements in RV/LV ratio (from 1.35 to 0.77), TAPSE, mean RVSP (from 50.35 to 28 mmHg), and PE quality-of-life score were observed.
Mechanical thrombectomy	Eid Lidt et al.46 (no control group)	52 patients	All eight patients (16.7%) with RVSP ≥40 mmHg by echocardiogram underwent ventilation-perfusion scans and tomography. CTEPD was confirmed in two (4.1%). Complete recovery of RV wall hypokinesis was noted in 79.1% of patients within 6 months.
	Ribas et al.47 (MT or CDT)	36 patients	After a median follow-up period of 9.6 months, 25 patients(69%) underwent imaging follow-up, showing residual pulmonary obstruction in 9 cases (36%). During the follow-up period, one patient (2.78%; 95% CI [0.1–14.5%]) developed CTEPH.
	PEERLESS48 (CDT versus MT)	550 patients (276 CDT and 274 FlowTriever)	Large-bore MT with the FlowTriever system showed better short-term outcomes (7 days) than CDT, due to lower clinical deterioration, reduced intensive care use and faster clinical and haemodynamic improvement at 24 h. No differences in mortality, intracranial haemorrhage, or major bleeding were observed.

6MWD = 6-min walk distance; AC = anticoagulation; CDT = catheter-directed thrombolysis; CTEPD = chronic thromboembolic pulmonary disease; CTEPH = chronic thromboembolic pulmonary hypertension; LV = left ventricle; MT = mechanical thrombectomy; PE = pulmonary embolism; RA = right atrium; RV = right ventricle; RVD = right ventricular dysfunction; RVSP = right ventricular systolic pressure; TAPSE = tricuspid annular plane systolic excursion; USAT = ultrasound-assisted thrombolysis.

Starting with systemic fibrinolytic therapy, although there are no studies specifically designed to assess PES incidence after acute PE, small studies have suggested that systemic fibrinolysis may reduce the risk of CTEPH. Nevertheless, a 3-year follow-up of PEITHO patients demonstrated similar rates of CTEPH in patients who received thrombolysis compared with those treated with anticoagulation. Additionally, there were no differences between groups regarding the frequency of RVD, functional limitations, or reduction in residual dyspnoea.39 In another small study with 83 patients, no difference was found in the frequency of right ventricular dilation or hypokinesis between groups at the 90-day follow-up.40

In the field of catheter-directed interventions (CDI), unfortunately, few studies have directly addressed the critical question of whether percutaneous techniques improve short- and long-term clinical outcomes after submassive PE. Most of the available reports involve small patient series, often without a control group and relying primarily on surrogate endpoints. As a result, drawing clinically meaningful and robust conclusions about the efficacy of these treatments is difficult, and the long-term effects on cardiopulmonary health remain uncertain.

Focusing on CDI, in the context of catheter-directed thrombolysis (CDT), the CANARY trial showed a reduction in the right-to-left ventricular (RV/LV) ratio, as measured on echocardiography, in patients treated with CDT compared with those in the control group, 72 hours after randomisation. However, there was no significant difference between the two groups 3 months after randomisation.41

Regarding the CDI group of studies available in the literature that have analysed the role of ultrasound-assisted thrombolysis (USAT) in this scenario, similar findings were observed. The ULTIMA trial demonstrated a significantly greater reduction in the right ventricle/right atrium (RV/RA) gradient with USAT compared with anticoagulation within 24 hours. However, no significant differences were found between the two groups in terms of the RV/RA gradient or the RV/LV ratio at 90 days.42 Another study involving 128 patients reported similar results, showing no echocardiographic or clinical benefit of CDI at mid-term follow-up.43

Additionally, a sub-analysis of the SUNSET sPE trial (a randomised study comparing anticoagulation with USAT for submassive pulmonary embolism) assessed 72 randomised patients. In that sub-analysis, both the 6-minute walk distance (6MWD) and the quality-of-life scores were comparable between the two groups at 3-month follow-up.44

However, the KNOCOUT PE trial, a prospective multicentre international registry of USAT in intermediate–high-risk and high-risk PE with 489 patients, did show significant differences with the use of USAT. At 3 months, improvements in the RV/LV ratio, tricuspid annular plane systolic excursion, mean right ventricular systolic pressure (RVSP) and PE quality-of-life score were observed. Unfortunately, that trial lacked a control group.45

Thus, none of these studies systematically investigated the incidence of CTEPH at 1–2-year follow-up, preventing the drawing of conclusions about whether these therapies modify the incidence of CTEPH.

In relation to mechanical thrombectomy (MT), the CDI that is undergoing a sudden increase in use, the following studies summarise the available evidence in the literature.

One CDI trial included 52 patients who underwent MT between 2004 and 2014.46 Those patients with estimated RVSP ≥40 mmHg as determined by echocardiogram during follow-up underwent ventilation–perfusion lung scans and tomography. CTEPH was confirmed in two out of eight patients, reflecting an incidence rate of 4.1%, which is consistent with previously reported figures. Furthermore, nearly 80% of the whole cohort had complete recovery of hypokinesis of the free right ventricular wall within the first 6 months.46 Similarly, comparable rates of CTEPH (2.78%) were reported in another trial involving 36 patients treated with either MT or CDT.47

In the recently published PEERLESS trial, the first randomised controlled study directly comparing two interventional strategies for PE, patients with acute intermediate-risk PE had better short-term outcomes (7 days) when treated with large-bore MT using the FlowTriever system (Inari Medical) compared with CDT.48 This benefit was driven by a lower incidence of clinical deterioration and/or need for rescue intervention, as well as reduced use of intensive care. Faster clinical and haemodynamic improvement at 24 hours was also observed with MT. However, there were no differences in mortality, intracranial haemorrhage, or major bleeding.48 Long-term follow-up of these cohorts will be necessary to assess whether CDI with MT or CDT shows differences in the rate of CTEPH or CTEPD compared with previous reports.

Thus, based on the available studies, the rate of CTEPH during follow-up does not significantly differ in patients with PE who undergo MT, particularly when compared with the overall incidence observed in patients with PE.

Furthermore, an analysis of 354 PEAs conducted at the University of California in 2021 and 2022 found that, of the 52 (15%) patients who had received CDI in the acute phase, 23 already had CTEPH when the technique was performed. CT findings provided crucial insights into the differences between acute and chronic disease. Features consistent with chronic disease included intraluminal webs, contracted vessels, eccentric thrombus, right ventricular hypertrophy, and collateral vessels, while supportive findings included lung mosaicism. In contrast, acute PE was characterised by thrombus located in the central portion of the vessel and a normal or expanded pulmonary artery.49

This highlights, on the one hand, the importance of patient selection, given that CDI is less effective when CTEPH is already present, with a non-negligible complication rate. On the other hand, it complicates the determination of the true rate of patients who will develop PES despite receiving CDI.

Therefore, an urgent need exists for randomised controlled trials (RCTs) comparing CDI with anticoagulation to assess their effects on long-term outcomes, such as mortality, and PES chronic complications. Fortunately, several RCTs are currently under way comparing CDI with anticoagulation alone, as summarised in Table 4.

Table 4: Ongoing Randomised Clinical Trials of Catheter-directed Intervention and Anticoagulation to Assess Effects on Long-term Outcomes.

Study	Study Design	Intervention/Control	n	Primary Outcome (Time)
HI-PEITHO50 (NCT04790370)	Randomised	USAT versus AC	406	Composite outcome of PE-related mortality, cardiorespiratory decompensation, non-fatal symptomatic PE recurrence (7 days); additional assessments at 30 days, 6 and 12 months, focusing on quality of life and functional outcomes.
PE-TRACT (NCT0591118)	Randomised	CDT or MT versus AC	500	Peak oxygen uptake (CPET) and patient-reported functional capacity (3 months and 1 year); first study to include CPET data in PE treatment.
PEERLESS II51	Randomised	Large-bore MT versus AC	1,200	Hierarchical composite outcome (all-cause mortality, clinical deterioration, readmission, bailout therapy, mMRC score) within 30 days; secondary outcomes include quality of life, 6MWD and post-PE impairment (up to 3 months).
STRATIFY (NCT04088292)	Randomised	USAT versus IV low-dose thrombolysis versus AC alone	210	Reduction in Miller score at 48–96 hours after randomisation; secondary outcome includes incidence of PH by echocardiography at 3 months.
VQPE (NCT05133713)	Observational prospective study	MT versus AC alone	50	Ventilation–perfusion mismatch via scintigraphy (6 months); secondary outcomes include 6MWD, dyspnoea and quality of life questionnaires (6 months).

6MWD = 6-min walk distance; AC = anticoagulation; CDI = catheter-directed intervention; CDT = catheter-directed thrombolysis; CPET = cardiopulmonary exercise testing; mMRC = modified Medical Research Council; MT = mechanical thrombectomy; PE = pulmonary embolism; PH = pulmonary hypertension; USAT = ultrasound-assisted thrombolysis.

HI-PEITHO (NCT04790370) is a global multicentre trial randomising patients with high-risk submassive PE to receive USAT plus anticoagulation versus anticoagulation alone. Patients are followed for 12 months, with assessments at multiple intervals. The primary outcome is a composite of PE-related mortality, cardiorespiratory decompensation or confirmed symptomatic PE recurrence within 7 days of randomisation. Additional assessments include bleeding complications, quality of life, functional status, and healthcare usage over the follow-up period. The trial aims to enrol 406 patients, with potential sample size adjustments based on interim analysis results.50

The PE-TRACT trial (NCT0591118) aims to evaluate whether CDI (either CDT or MT) improve cardiopulmonary health over 1 year post-PE compared with anticoagulation alone, with plans to enrol 500 patients. Primary outcomes will be assessed at 3 months and 1 year, focusing on peak oxygen uptake (via CPET) and patient-reported functional capacity, to evaluate the therapies’ impact on PES. This study, the first to include CPET data, addresses a key gap regarding the effects of CDI on PES. Enrolment began in July 2023, with completion expected by 2026 and publication by 2028.

The PEERLESS II trial, currently recruiting 1,200 patients, evaluates outcomes in intermediate-risk PE patients treated with large-bore MT and anticoagulation versus anticoagulation alone. Primary endpoints focus on the first month after the event, including a composite win ratio of all-cause mortality, clinical deterioration, hospital readmission, bailout therapy, and modified Medical Research Council dyspnoea score ≥1 at 48 hours. Secondary endpoints cover mortality, readmissions, bleeding, clinical deterioration, RV/LV ratio, dyspnoea scores, quality of life, 6MWD and post-PE impairment diagnosis at various follow-up points (30 days–3 months).51

The STRATIFY trial (NCT04088292) is an open-label, randomised study comparing three management strategies for acute intermediate–high-risk PE: USAT, low-dose intravenous thrombolysis, and anticoagulation alone. It aims to enrol 210 patients with a 1:1:1 allocation. The primary objective is to assess the reduction in Miller score at 48–96 hours after randomisation between the low-dose thrombolysis and the heparin-only groups, and between low-dose thrombolysis and USAT. A secondary objective is to evaluate the incidence of PH via echocardiography at 3 months, helping to determine the impact of these therapies on CTEPH incidence following PE.

The VQPE trial (NCT05133713) aims to compare thrombotic load at 6 months after an acute episode, enrolling 50 patients. Primary assessments will include ventilation–perfusion mismatch using scintigraphy at 6 months. Secondary objectives include 6MWD, a dyspnoea questionnaire and evaluation of quality of life, all to correlate thrombotic load with PES.

Thus, in the near future, some of these complementary trials will hopefully help define the role of catheter therapies in submassive PE and their usefulness in preventing PES.

Conclusion

Morbidity and mortality in PE remain high despite current intervention guidelines, with a significant incidence of long-term complications. Chronic complications are often grouped under PES, a condition affecting more than half of PE survivors. PES is linked to several serious outcomes, including CTEPH, CTEPD, RVD, physical deconditioning, and psychological harm: conditions that substantially reduce quality of life and functional capacity. While catheter-directed therapies have been shown to have short-term effectiveness in high-risk PE cases, their role in preventing PES over long-term follow-up remains unclear. Further research on catheter-directed treatments is needed to better understand their potential in preventing these secondary conditions, with this area of study expected to expand significantly in the near future.