Recent advances in risk stratification and treatment of acute pulmonary embolism

Abstract

Pulmonary embolism (PE) represents the third leading cause of cardiovascular death, despite the implementation of European Society of Cardiology guidelines, the establishment of PE response teams and advances in diagnosis and treatment modalities. Unfavorable prognosis may be attributed to the increasing incidence of the disease and pitfalls in risk stratification using the established risk stratification tools that fail to recognize patients with intermediate-high risk PE at normotensive shock in order to prevent further deterioration. In this light, research has been focused to identify novel risk stratification tools, based on the hemodynamic impact of PE on right ventricular function. Furthermore, a growing body of evidence has demonstrated that novel interventional treatments for PE, including catheter directed thrombolysis, mechanical thrombectomy and computer-assisted aspiration, are promising solutions in terms of efficacy and safety, when targeted at specific populations of the intermediate-high- and high-risk spectrum. Various therapeutic protocols have been suggested worldwide, regarding the indications and proper timing for interventional strategies. A ST-elevation myocardial infarction-like timing approach has been suggested in high-risk PE with contraindications for fibrinolysis, while optimal timing of the procedure in intermediate-high risk patients is still a matter of debate; however, early interventions, within 24-48 hours of presentation, are associated with more favorable outcomes.

Key Words: Acute pulmonary embolism; Interventional treatment; Catheter-directed treatments; Thrombolysis; Risk stratification; Pulmonary embolism response team

Core Tip: Pulmonary embolism remains a major clinical challenge with unacceptably high mortality, especially in intermediate-high risk patients. Despite major advances in risk stratification, identifying stable patients at risk of decompensation remains unsolved. Emerging catheter-based therapies prove promising and safe, but proper patient selection and optimal timing require further investigation. A multidisciplinary approach is crucial for improving outcomes, while future research should focus on validating risk tools, standardizing protocols, and evaluating hard clinical endpoints in interventional trials.

INTRODUCTION

Acute pulmonary embolism (PE) still represents the third most common cause of cardiovascular death globally despite the implementation of the recent European Society of Cardiology (ESC) guidelines, the establishment of PE response teams (PERT) and advances in diagnosis and treatment modalities over the years in terms of diagnosis and medical treatment of PE[1,2]. On the other hand, the incidence of the disease seems to exhibit an increasing trend probably due to higher clinical suspicion, better diagnostic yield of modern imaging modalities and potentially as a thromboembolic fingerprint of coronavirus disease 2019 (COVID-19) pandemic[3-6]. Contemporary risk stratification tools pose significant pitfalls in timely identifying intermediate-high risk patients at imminent hemodynamic deterioration[7] and novel risk stratification tools are being investigated, based on right ventricular (RV) function. Furthermore, a growing body of evidence has demonstrated that novel interventional treatments for PE are promising solutions in terms of efficacy and safety, when targeted at specific populations of the intermediate-high and high-risk spectra. However, robust evidence on hard endpoints is still anticipated from the ongoing randomized clinical trials in order to establish a role of these advanced therapeutic options in common clinical practice[8-14]. In this regard, therapeutic protocols worldwide vary significantly, regarding patient selection and proper timing for interventional strategies. According to a recent ESC consensus document, even a ST-elevation myocardial infarction (STEMI)-like timing approach is suggested in high-risk PE with contraindications for fibrinolysis, while optimal timing of the procedure in intermediate-high risk patients is still a matter of debate[15]. Optimal recovery of PE patients warrants a systematic follow-up strategy addressing immediate and long-term complications through a multidisciplinary holistic approach[16].

INCIDENCE AND PROGNOSIS OF ACUTE PE

The annual incidence PE ranges from 39-115 per 100000 population[1]. A tertiary hospital serving a population of 500000 typically admits around six patients with PE each month. Making matters worse, the incidence of the disease seems to exhibit an increasing trend probably due to higher clinical suspicion, better diagnostic tools, and the well described thromboembolic complications of COVID-19[3-5]. A recent cross-sectional study of emergency department visits in the United States during the period 2016-2023 identified a PE diagnosis prevalence of 0.29% across over 186 million encounters. It should be noted that PE diagnoses represented 0.20% of total admissions in 2016 and peaked at 0.35% in 2021, potentially owing to the high awareness in the setting of COVID-19 pandemic[6].

Despite the major advancements in diagnosis and medical treatment, 30-day mortality rates according to recent registries reach 30% for the high-risk cases[2,17] and up to 5% to 15% for the intermediate-high risk ones[7,18-20]. Additionally, survivors of an acute PE episode face an important risk of recurrent thromboembolic events, symptoms of heart failure, post-PE syndrome and development of chronic thromboembolic pulmonary hypertension (CTEPH)[16,21].

GUIDELINE DIRECTED MEDICAL TREATMENT OF ACUTE PE

According to 2019 ESC Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism[22], patients with PE are risk stratified for severity and early mortality (in-hospital and 30-day) in three major risk groups based on hemodynamic status, major clinical parameters incorporated in PE severity index (PESI) or its simplified version (sPESI), RV dysfunction assessed by echocardiography or computed tomography pulmonary angiogram (CTPA), levels of cardiac troponin, and further management is guided accordingly. Patients with prevalent hemodynamic compromise consist of the high-risk category and require urgent intravenous systemic thrombolysis (if such a treatment is not contraindicated). On the opposite side belong patients suffering PE with no cardiovascular impact (no evidence of hemodynamic instability, PESI class I-II or sPESI = 0, preserved RV function). Those are considered low-risk and may be treated even on an outpatient basis. Intermediate risk group (PESI class III-IV or sPESI ≥ 1 ± evidence of RV dysfunction/elevated cardiac troponin) represents a challenging spectrum. This category includes stable patients with minor cardiovascular impact (intermediate-low risk), as well as patients with higher clot burden, often radiologically defined as massive, who do not present with shock [systolic blood pressure (SBP) < 90 mmHg] and may have a favorable prognosis on conservative treatment (intermediate-high). The suggested first line treatment strategy for the intermediate risk group is low molecular weight heparin or even direct oral anticoagulants (DOACs), whereas reperfusion treatments, including systemic thrombolysis, interventional or surgical treatment, are reserved as bail-out solutions in case of clinical deterioration.

CHALLENGES IN RISK STRATIFICATION

Evidence-based risk stratification is of paramount importance in acute and potentially life-threating conditions such as PE in order to guide optimal management. Several tools have been developed through clinical trials, registries and other academic initiatives, each tailored to evaluate different aspects of PE severity and estimate usually early mortality (in-hospital and 30-day)[23-34] (Table 1).

Table 1 Comparison of risk stratification models and parameters in acute pulmonary embolism.

Ref.	Risk model/marker	Clinical application	Clinical use	Statistical performance	Advantages	Limitations
Aujesky et al[23], 2005	PESI	30-day mortality	Risk stratification for 30-day mortality	95% sensitivity, 38% specificity (for PE mortality)[24]	Only clinical assessment	Multiple parameters, no assessment of RV strain, low specificity
Jiménez et al[25], 2010	sPESI	30-day mortality, 30-day recurrent VTE/PE or bleeding	Simpler alternative to PESI	96% sensitivity, 37% specificity (for PE mortality)[24]	Simple and fast	No assessment of RV strain, low specificity
Zondag et al[26], 2011	Hestia criteria	Low-risk patients identification	Determines eligibility for outpatient management	82% sensitivity, 56% specificity (low-risk identification)[27]	99% negative prognostic value, solid validation data	Only low-risk assessment
Bova et al[28], 2014	BOVA score	30-day clinical deterioration and mortality	Identifies patients who may need escalated care	AUROC = 0.73, 95%CI: 0.68-0.77 (PE complication prediction)	Incorporates RV dysfunction, separates normotensive PE SBP > 90 mmHg from > 100 mmHg	Requires imaging and blood tests
Vanni et al[29], 2013	Plasma lactate	Clinical deterioration and 30-day mortality	Helps identify normotensive shock	HR = 11.67; 95%CI: 3.32-41.03 (all cause 30-day mortality)	Identifies hypoperfusion, thus true hemodynamic impact	Used supplementary to enhance risk models, requires sequential ABG assessment
Otero et al[30], 2007	Shock index	30-day mortality	Used in risk stratification for hemodynamic instability	SI vs SBP < 90 mmHg; specificity: 86.3% vs 96.6%, sensitivity: 30.5% vs 7.9%	Improves hemodynamic assessment	Lower specificity compared to SBP < 90 mmHg, limited value in hypertensive patients
Grade Santos et al[31], 2022	NEWS score	Clinical deterioration and 30-day mortality	Used in hospitalized patients for early detection of worsening PE	Greater predictive power compared to PESI (OR = 1.35; 95%CI: 1.11-1.64, P = 0.003 vs OR = 1.02; 95%CI: 1.00-1.03, P = 0.03)	Already widely used and validated in various health systems	Not specific for PE
Meinel et al[32], 2015	RV/LV ratio (CTPA)	Mortality and adverse outcomes up to 6 months	Predicts PE outcomes by RV dysfunction assessment	All-cause mortality (OR = 2.5; 95%CI: 1.8-3.5)	Calculated from CTPA if echocardiography is not available	Requires imaging
Pruszczyk et al[33], 2014	TAPSE	30-day mortality or need for rescue thrombolysis	Predicts PE outcomes by RV dysfunction assessment	Better AUC compared to RV/LV ratio (0.91, 95%CI: 0.856-0.935; P = 0.0001 vs 0.638, 95%CI: 0.589-0.686; P = 0.001)	Single parameter compared to RV/LV	Requires echocardiography
Kiamanesh et al[34], 2022	TAPSE/PASP ratio (RV-PA uncoupling)	Adverse events in normotensive PE	Predicts PE outcomes by RV-PA uncoupling	For each 0.1 mm/mmHg decrease in TAPSE/PASP (adjust OR = 2.49, 95%CI: 1.46-4.24, P = 0.001)	Allows the assessment of the true hemodynamic impact of PE in RV function	Requires echocardiography, limited evidence in PE

PESI: Pulmonary embolism severity index; sPESI: Simplified pulmonary embolism severity index; NEWS: National Early Warning Score; TAPSE: Tricuspid annular plane systolic excursion; PE: Pulmonary embolism; VTE: Venous thromboembolism; TAPSE: Tricuspid annular plane systolic excursion; PASP: Pulmonary artery systolic pressure; RV: Right ventricle; RV/LV ratio: Right ventricular to left ventricular diameter ratio; PA: Pulmonary artery; OR: Odds ratio; HR: Hazard ratio; CI: Confidence interval; AUROC: Area under the receiver operating characteristic curve; CTPA: Computed tomography pulmonary angiogram; SBP: Systolic blood pressure.

Most risk models define high-risk patients by hemodynamic instability, including shock or hypotension. Further risk stratification in apparently hemodynamically stable patients is usually based on age, major clinical parameters and comorbidities, as well as cardiac biomarkers (troponin, NT-proBNP) and imaging (echocardiographic and/or CTPA) signs of RV dysfunction. The ESC Guidelines integrated these features into a three-tier risk model (high, intermediate, low) as already described. The widely used PESI score was introduced in 2005 to predict 30-day mortality based on clinical parameters such as age, comorbidities, and vital signs. Both PESI and sPESI proved practical and effective in daily clinical practice, thus were incorporated in ESC guidelines suggested risk stratification model[23,35].

Hestia criteria comprise a risk model that reliably identifies low risk patients who can safely be treated on an outpatient basis since the lack of any suggested criteria is strongly associated with lower than 1% mortality and 2% possibility of venous thromboembolism recurrence within 3 months[26]. Both sPESI and Hestia scores show remarkable utility in selecting low risk patients with nearly optimal sensitivity and negative predictive values (82% and 99% for the Hestia criteria and 91% and 100% for sPESI, respectively) simply by assessing clinical parameters and comorbidities[27]. On the other hand, BOVA score focuses on the intermediate risk group and proves superior in identifying higher risk patients that may benefit from closer monitoring and escalated treatment by incorporating biomarkers (troponin) and markers of RV dysfunction, which add separate points to the score. Furthermore, although it is applicable to normotensive patients, an SBP of 90-100 mmHg reclassifies patients to a higher risk[28].

In addition to the aforementioned risk models, newer markers and scoring systems are increasingly investigated and used in treatment protocols worldwide. Plasma lactate levels, which indicate the impact of cardiac output in tissue perfusion, have emerged as a significant predictor of adverse outcomes in acute PE. Plasma lactate ≥ 2 mmol/L has been associated with increased 30-day mortality and risk of clinical deterioration independently of hemodynamic status, RV dysfunction, or elevated cardiac biomarkers[29].

Shock index (SI), is a simple marker of hemodynamic compromise calculated as the ratio of heart rate to SBP. In the RIETE registry SI was a potent predictor of 30-day mortality[30]. Many protocols suggest the estimation of SI in the initial assessment of normotensive PE patients, with values > 1 warranting more aggressive management. The National Early Warning Score is also gaining attention in PE management. This scoring system, which is a comprehensive assessment of vital signs, is widely used in patients hospitalized in wards in order to timely identify clinical deterioration. In recent studies, National Early Warning Score assessment in patients with intermediate-high risk PE has demonstrated greater predictive power for the composite endpoint of 30-day cardiovascular mortality, rescue thrombolysis and/or hemodynamic instability compared to the PESI score and authors suggested its incorporation in ESC risk stratification[31,36].

Focusing on the role of imaging, markers of RV dysfunction are well-established indicators of PE severity and predictors of outcomes either assessed by echocardiography or by CTPA. In particular, RV/left ventricular (LV) ratio of ≥ 1 has been associated with increased mortality regardless of the method of assessment[32,33]. Another echocardiographic parameter related to worse outcomes in acute PE is tricuspid annular plane systolic excursion (TAPSE) < 16 mm[33]. More reliable echocardiographic markers of RV dysfunction are being investigated for their predictive value in acute PE, including RV fractional area change, RV strain[37,38]. However, since they are derived from advanced imaging, their practicality is questioned in the emergency setting. A promising tool is the assessment of RV-pulmonary artery (RV-PA) uncoupling, estimated by the ratio of TAPSE/PA systolic pressure, which has already been thoroughly investigated in the fields of pulmonary hypertension and heart failure[39,40]. In case of significant RV-PA uncoupling during an acute PE, RV is unable to overcome the increased pulmonary afterload due to severe systolic compromise, leading to critically reduced cardiac output and potential collapse. Taking into account the pathophysiological rationale, TAPSE/PA systolic pressure may prove a potent predictor of clinical deterioration and worse outcomes[34].

Concomitant conditions like patent foramen ovale/atrial septal defect or even the rare finding of thrombus in transit dramatically increase morbidity and mortality risk of an acute PE event[41,42]. The presence of concomitant deep vein thrombosis (DVT) has been independently associated with increased 3-month mortality[25]. Recently, Bangalore et al[7] developed a 6-factor risk prediction model able to reliably identify patients at imminent hemodynamic compromise (normotensive shock) based on the intermediate-high risk population of FLASH registry. Prognostic factors included were tachycardia, elevated biomarkers, echocardiographic proof of RV dysfunction as well as angiographic severity of PE (saddle PE) and concomitant DVT[7].

NORMOTENSIVE SHOCK: A HIDDEN ENEMY

As already stated, the intermediate risk group is diverse, including both at the verge of low and high risk. However, a noteworthy consideration in managing the latter group is the potential for normotensive shock, a condition in which patients maintain near-normal blood pressure yet experience significant hemodynamic compromise due to severe RV strain and subsequently reduced cardiac output and tissue perfusion (SBP > 90 mmHg but with a reduced cardiac index of ≤ 2.2 L/minute/m²).

In the recent FLASH registry, 34% of patients with intermediate-high risk PE (per definition with normal blood pressure) were shown to be in normotensive shock, which was associated with increased morbidity due to the higher risk of further hemodynamic deterioration and eventual collapse[7]. This finding underscores the importance of vigilant monitoring and early interventional reperfusion treatment aiming to rapidly reduce clot burden and relieve RV strain, potentially preventing progression to full blown shock and its associated complications leading to increased mortality.

Of note, as already mentioned, increased plasma lactate levels can also unveil a reduction of cardiac output and tissue perfusion compatible with normotensive shock and they have been associated with adverse outcomes in acute PE[29]. Several cathlabs have adopted similar strategies to timely identify patients at normotensive shock as candidates for emergent interventional management with impressive outcomes as reported in case reports and series[43,44].

IMPLEMENTATION OF PERTS

The concept of PERTs was introduced in 2012 at Massachusetts General Hospital by a multidisciplinary medical team aiming to improve the outcomes of acute PE. PERT composition can involve clinical and interventional cardiologists, pulmonologists, critical care and emergency medicine physicians, hematologists, radiologists, even cardiac surgeons. The main goal of this multidisciplinary approach is to provide optimal decision-making, holistic care and timely access to advanced treatments such as thrombolysis, catheter-based therapies, or surgical embolectomy for patients with intermediate- and high-risk PE.

Starting from emergency medicine physicians, they are instrumental in early diagnosis, initial risk stratification, and PERT activation. Alongside are imaging specialists, including radiologists, who ensure accurate diagnosis through CTPA. Cardiologists play a central role in assessing RV dysfunction, managing hemodynamic instability, and guiding catheter-directed interventions. Pulmonologists focus on evaluating pulmonary function and monitoring long-term complications such as post-PE syndrome and CTEPH. Critical care specialists provide advanced hemodynamic monitoring and support, particularly in patients with high-risk PE requiring intensive management. Hematologists contribute by guiding anticoagulation strategies, assessing thrombophilia risk, and determining the duration of anticoagulant therapy. Finally, cardiac surgeons are consulted in cases requiring surgical embolectomy when medical and catheter-based treatments are insufficient.

The real word function of PERTs has shown significant improvements in clinical outcomes for patients with intermediate- and high-risk PE. Evidence from observational studies and meta-analytic data demonstrate that PERT implementation reduces 30-day mortality even by up to 75%. Additionally, PERTs shorten hospital length of stay (median reduction from 9 to 4 days) and lower in-hospital bleeding complications, while increasing the access to advanced treatment modalities[45,46]. Since its inception, the PERT protocol has been embraced worldwide, recognized as the gold standard model for the optimal management of severe PE. Recently it was endorsed in the ESC Guidelines in an effort for further implementation, in order to improve outcomes, reduce hospital stays, and refine decision-making in acute and complex clinical scenarios.

INTERVENTIONAL TREATMENT FOR ACUTE PE

According to the 2019 ESC Guidelines[22], reperfusion treatments - including interventional approaches such as catheter-directed thrombolysis, mechanical thrombectomy, computer-assisted aspiration, and surgical embolectomy - are reserved as bailout options for intermediate-risk patients experiencing clinical deterioration or for selected high-risk cases where systemic thrombolysis has either failed or is contraindicated. However, over the last years, a growing body of evidence supports catheter directed treatments (CDT) as a viable first line therapeutic approach for patients with intermediate-high risk PE at risk of RV dysfunction and associated complications and high-risk PE patients with contraindications for thrombolytics (Table 2).

Table 2 Major trials of interventional treatment for acute pulmonary embolism[48].

Ref.	Trial name	Device	Design	Population	Pe risk category	Intervention	Control	Outcomes	Follow up
[9]	FLARE, 2019	FlowTriever	Single-arm	106	Intermediate-risk, PE	Anticoagulation plus FlowTriever	-	∆RV/LV ratio at 48 hours: 0.41 ± 0.05 (P < 0.0001)/0 all-cause deaths/major bleeding: 0.9% at 48 hours	30 days
[11]	EXTRACT-PE, 2021	Indigo	Single-arm	119	Intermediate-risk	Anticoagulation plus Indigo	-	∆RV/LV ratio at 48 hours: 0.43 ± 0.26 (P < 0.0001)/all-cause death: 1.1%; major bleeding: 1.6% at 48 hours	30 days
[13]	SEATTLE II, 2015	EkoSonic	Single-arm	150	Intermediate high-risk PE	Anticoagulation plus tPA-USAT (12-24 mg)	-	∆RV/LV ratio at 48 hours: 0.42 ± 0.36 (P < 0.0001)/7 deaths, 15 major bleeds at 30 days	30 days
[10]	OPTALYSE PE, 2018	EkoSonic	Randomised, open-label	101	Intermediate high-risk PE	Anticoagulation plus tPA-USAT (4 mg, 6 mg, or 12 mg)	Compared 4 tPA regimens	RV/LV ratio reduced in all arms at 48 hours/5 major bleeds at 72 hours	365 days
[14]	FLAME, 2023	FlowTriever	Prospective, non-randomised	104	High-risk PE	Anticoagulation plus FlowTriever	Other therapies	Composite of all-cause mortality, clinical deterioration, bailout, and major bleeding: 17% vs 63.9%/all-cause death: 1.9% vs 29.5%; major bleeding: 11.3% vs 24.6%	In hospital
[46]	PEERLESS, 2024	FlowTriever	Open-label	550	Intermediate high-risk PE	FlowTriever	Catheter directed thrombolysis	Primary composite win ratio: 5.01 (P < 0.001) driven by fewer clinical deteriorations and reduced ICU utilization/all-cause death: 0% at discharge/no increase in ICH or major bleeding	7 days

PE: Pulmonary embolism; LV: Left ventricular; RV: Right ventricular; tPA: Tissue plasminogen activator; USAT: Ultrasound-assisted thrombolysis; ICU: Intensive care unit; ICH: Intracranial bleeding.

In particular, the SEATTLE II and OPTALYSE PE trials using ultrasound-assisted catheter directed thrombolysis via EkoS system, the EXTRACT-PE trial studying computer-assisted aspiration using Indigo system, and the FLARE and FLAME trials, which assessed mechanical thrombectomy using the FlowTriever system, all showed rapid and significant reductions in RV/LV ratio and PA pressure with low rates of major bleeding[8-11,13,14]. Despite offering promising results, the single arm design of most and the surrogate endpoints that were primarily assessed did not provide solid evidence to justify the routine implementation of CDT in the treatment of intermediate-high risk PE. However, real world data of large registries such as FLASH[12], demonstrated for the first time significant reductions in morbidity and mortality outcomes.

Of great interest were the recently published primary results of PEERLESS randomized trial, which compared mechanical thrombectomy using the FlowTriever system with catheter-directed thrombolysis in patients with intermediate-high risk PE. Large bore mechanical thrombectomy was associated with lower rates of clinical deterioration and bailout treatment and postprocedural intensive care unit stay, whereas no difference was observed in mortality or bleeding[47]. In the same line, randomized control trials such as the PEERLESS II study[48] are being conducted to compare CDT vs conservative guideline directed medical treatment in this group of patients in terms of efficacy and safety studying for the first time hard endpoints of clinical interest.

In light of these promising data, the use of CDT for PE has significantly increased from 1.7% in 2016 to 3.2% in 2020[49]. The main reason for this warm embrace is that CDT emerged in most studies and real-world registries as a safe and effective treatment for intermediate- and high-risk PE. However, as with every interventional method, they are not without risks. Adverse event type and frequency vary by modality but the most commonly described are bleeding complications including minor bleeding in 10%-25% of cases usually related to vascular access, major bleeding (gastrointestinal and retroperitoneal) in less than 10% related to access and anticoagulation and very rarely intracranial hemorrhage (less than 1%). Vascular access complications come second in 5%-10% of cases, including hematomas, arterial puncture, pseudoaneurysms, or infections at the access site. Device-related complications are rarely seen (1%-3%) with the most severe being pulmonary vascular rupture. A fortunately uncommon but potentially fatal complication is pulmonary reperfusion injury. In this scenario, patients exhibit an acute respiratory distress syndrome-like condition caused by the rapid reperfusion of ischemic lung tissue analogous to coronary reperfusion injury in the setting of STEMI. Although the adverse events should be acknowledged, their incidence is much lower compared to the bleeding consequences of systemic thrombolysis. Risk factors, such as older age, frailty, comorbidities, and concurrent anticoagulant therapy, can increase their likelihood[50].

TIMING PROTOCOLS FOR CDT

Advances in the treatment of acute myocardial infarction have been based on the concept that time is myocardium and reperfusion therapy has long been established. Solid evidence has defined the strict time frames for the optimal management of STEMI, whereas in the case of NSTEMI timing suggestions are less clear, although still based on risk stratification. Similarly to myocardial infarction, reperfusion therapy in PE is considered in order to rapidly restore pulmonary blood flow, improve gas exchange, and restore RV function, with high-risk PE exhibiting an analogous to STEMI time-dependent benefit with improved in-hospital mortality and less recurrent PE if thrombolytic therapy is initiated within 1 hour of diagnosis[51,52].

Recent CDT trials have provided promising results in terms of safety and efficacy of interventional treatments, although data from randomized clinical trials are still missing. This has led to the gradual adopting of interventional modalities in cathlabs worldwide and their implementation in local PE treatment protocols. High risk patients with contraindications for thrombolysis or treatment failure not only pose an indication but in fact depend on emergent access to CDT as a non-surgical bailout solution. However, proper patient selection and timing of CDT in the setting of intermediate-high risk PE remains unanswered and either varies by protocol or is personalized according to the centers’ experience.

A systematic review including 6 studies and 306 patients suggested for the first time a favorable impact of early interventions (< 24-48 hours after presentation) compared to a delayed (> 48 hours) approach. Improved outcomes involved the usual surrogate markers of reduction in pulmonary arterial pressures and RV/LV ratio and low rates of procedural complications and mortality. However, several limitations were noticed since only 2 of the trials attempted a direct comparison of early and delayed CDT. The study population was very limited and included both intermediate-high and high-risk patients with no separate analysis, and the time to treatment initiation from symptom onset varied significantly, reaching even 14 days. The authors, conclude, however, with a very apposite remark, suggesting that a door-to-cath time is more warranted in high-risk patients who are likely to benefit from an emergent intervention due to hemodynamic compromise[53].

As evidence continues to grow, the timing of CDT has recently been addressed in a consensus statement by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. Despite the limited data, the Taskforce noted that for high-risk patients, adopting a STEMI-like approach is reasonable once the PERT establishes indications for CDT. Specifically, patients already admitted to a CDT-capable center should undergo the procedure within 60 minutes of the CDT indication (not the initial diagnosis). For patients at non-CDT centers, transfer to a CDT-capable facility should ideally occur within 90 minutes. Nevertheless, systemic thrombolysis remains the first-line treatment if not contraindicated[15,49].

For the more debated group of intermediate-high risk PE patients, CDT is recommended only when no significant improvement is observed after 24-48 hours of initial anticoagulation, consistent with the aforementioned review. However, strict adherence to this timeline is not mandatory. During this period, PERT should use the time to reassess the need for CDT and coordinate logistics for potential escalation of care[15,49]. Regardless of the final decision for the treatment plan, it would seem reasonable to consider transfer of selected intermediate-high risk patients to referral centers with onsite PERTs, experience in clinical management and emergent access to reperfusion treatments in order to improve outcomes[52].

OPTIMAL FOLLOW-UP ALGORITHM

Optimal follow-up for PE patients has long been a matter of debate and management strategies are often personalized. The first attempt to provide comprehensive guidance was recently published by Klok et al[16] as a position statement by ESG Working Group on Pulmonary Circulation and Right Ventricular Function in collaboration with ESG Working Group on Atherosclerosis and Vascular Biology. They recommend a holistic approach that addresses both immediate and long-term needs, with follow-up checkpoints at time of diagnosis, within the first month, at 3 months and further long-term. Provided guidance is focused in the following 5 main pillars: Bleeding and cardiovascular risk assessment, screening for thrombophilia and cancer, tailored approach to female sex, sport-lifestyle-travel, assessment and management of long-term PE consequences such as post-PE syndrome and CTEPH (Table 3).

Table 3 Suggested optimal follow-up algorithm in pulmonary embolism.

Time point	Assessments/actions	Key considerations/notes
Index event	Baseline clinical assessment. Perform cancer screening (clinical exam, basic labs, chest imaging via CTPA). Bleeding and CV risk assessments	Imaging (e.g., CTPA) is typically available. Begin addressing reproductive considerations for female patients where applicable
4-6 weeks	Conduct follow-up visit(s) for continued bleeding risk assessment. Reassess CV risk. Plan for thrombophilia screening (deferred until 4-6 weeks to avoid false results, especially if on DOACs)	Adjust anticoagulation treatment based on modifiable bleeding risk factors. Thrombophilia screening (especially for antiphospholipid syndrome) should be considered in unprovoked cases
At 3 months	Evaluate functional status and quality of life. Perform CPET if symptoms persist. Screen for post-PE syndrome (new/progressive dyspnea, exercise intolerance). Assess for CTEPH in patients with persistent symptoms	Post-PE syndrome may affect 40%-60% of survivors. CTEPH (affecting 2%-3%) should be ruled out in patients with ongoing dyspnea or right heart failure; referral to expert centers is advised
Long-term follow-up	Periodic follow-up visits: Bleeding and CV risk assessment. Monitor for long-term complications (post-PE syndrome, CTEPH). Provide tailored management for female patients (pregnancy planning, contraceptive guidance). Advise on gradual resumption of physical activity and appropriate travel (e.g., use compression stockings and on-demand prophylactic anticoagulation for long air travel when indicated)	Lifestyle counseling remains crucial for recovery. Regular monitoring ensures timely intervention for evolving complications

CTPA: Computed tomography pulmonary angiogram; CV: Cardiovascular; DOACs: Direct oral anticoagulants; CPET: Cardiopulmonary exercise testing; CTEPH: Chronic thromboembolic pulmonary hypertension.

In particular, bleeding risk assessment is suggested at all follow-up visits or until coagulation treatment is terminated in order to timely deal with modifiable bleeding risk factors and potentially reconsider treatment regime and duration. Cardiovascular risk assessment is proposed due to solid evidence demonstrating a two- to threefold increased incidence of arterial cardiovascular disease in patients with PE or DVT compared to matched general population[54,55]. Concomitant cardiovascular disease (coronary artery disease, valvular disease, atrial fibrillation, peripheral arterial disease) may crucially impact treatment decisions and antithrombotic drug regimes in PE patients.

A holistic approach is suggested for female patients with a reproductive potential throughout the follow-up period focusing on matters of pregnancy and especially when PE is contraceptive related. For the category of patients, screening threshold for acquired and inherited thrombophilia should be low[56]. Regarding thrombophilia screening, it should be deferred at the acute and subacute phase (4-6 weeks) due to false positive and negative results and care should be given to not perform it on treatment with DOACs[57]. Antiphospholipid syndrome screening is cost-effective and can alter treatment decisions since DOACs are not indicated[58,59]. Therefore, it should be considered in all patients with unprovoked PE, and especially in case of prior arterial or small-vessel thrombosis, pregnancy complications, autoimmune diseases or age < 50 years. The Taskforce strongly advises against routine screening for genetic thrombophilia except for patients < 50 years old, with unprovoked PE and relevant family history.

Cancer screening is reasonable to be performed during hospitalization and should include a thorough clinical assessment, basic laboratory testing. Chest imaging is usually available de facto by CTPA. Age and gender-specific testing for common malignancies should be implemented in accordance with national guidelines and protocols. Red flags that warrant cancer screening are prior history of a considered as cured cancer, venous thromboembolism recurrence on anticoagulant treatment, and gastrointestinal or urinary tract anticoagulant-related early bleeding[60]. Diagnosing cancer could impact prognosis and alter treatment decisions. Limited cases warrant further assessment with abdomen computed tomography or more advanced imaging modalities, due to lack of data in regards of prognostic benefit[61].

The authors emphasize the importance of monitoring for CTEPH and they advocate for evaluating functional status and quality of life to detect post-PE syndrome early, starting from 3-months after the index event. CTEPH, although quite uncommon (2%-3%) should be suspected and ruled-out in all PE patients with persistent symptoms of dyspnea or right heart failure despite 3 months of anticoagulation and patients should be referred in expert center for a thorough evaluation and management[62,63]. Routine testing for CTEPH is not recommended in asymptomatic patients, however, the index event imaging test (CTPA, echocardiogram) should be used to detect latent signs of CTEPH. On the other hand, post-PE syndrome is commonly described (40%-60% of PE survivors)[63,64]. It is defined as new or progressive dyspnea, exercise intolerance, and/or impaired functional or mental status after at least 3 months of anticoagulation, not primarily attributed to prevalent comorbidities. In this case, performance of cardiopulmonary exercise testing is strongly indicated. Post-PE patients should receive a multidisciplinary approach and be referred to cardiorespiratory rehabilitation and phycological support programs.

Last but not least, PE patients should be encouraged to gradually return to regular physical activity and adopt a healthier lifestyle. Strenuous exercise and air travel should be avoided until the complete recovery of RV function. Focusing on long air travel (> 4 hours), patients who discontinue anticoagulation treatment seem to benefit from prophylactic use of compression stockings and on demand anticoagulation at prophylactic dose[65,66].

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

The evolving landscape of PE management necessitates a structured and multidisciplinary approach to optimize patient outcomes. The integration of PERTs has significantly improved clinical decision-making, yet challenges remain in refining risk stratification, standardizing interventional strategies, and improving access to advanced therapies across different healthcare settings. One of the most pressing clinical implications is the identification and management of patients with normotensive shock, a high-risk subgroup within the intermediate-high-risk category. While traditional risk models primarily focus on hemodynamic instability, emerging evidence suggests that normotensive patients with signs of RV strain, elevated cardiac biomarkers, and systemic hypoperfusion may benefit from early intervention[7]. Future research should aim to establish standardized criteria for diagnosing normotensive shock and determining its threshold for escalation to CDT.

With the increasing adoption of CDT as an alternative to systemic thrombolysis, particularly in patients with contraindications, the optimal timing of intervention remains an area of active investigation. The existing literature suggests that early intervention, within 24-48 hours of presentation, may yield better outcomes in intermediate-high-risk PE patients who fail to show improvement with anticoagulation alone[49]. However, randomized controlled trials are needed to establish firm recommendations. The PEERLESS trial has provided initial insights into the efficacy of large-bore mechanical thrombectomy vs catheter-directed thrombolysis, but additional studies comparing CDT with standard anticoagulation will further define its role in treatment algorithms[47]. Additionally, future investigations should assess whether a STEMI-like approach, with a “door-to-intervention” time model, could enhance outcomes in high-risk PE patients who are ineligible for systemic thrombolysis.

Another critical area for future research is the refinement of risk stratification models through the incorporation of novel biomarkers and imaging parameters. Traditional models, such as the PESI and the sPESI, primarily rely on clinical parameters and comorbidities but lack precision in predicting early hemodynamic deterioration. Newer predictive markers, including plasma lactate levels, SI, and RV-PA uncoupling, have shown promise in identifying high-risk patients who may require more aggressive treatment. Future studies should focus on integrating these parameters into existing risk models and validating them in large, prospective cohorts.

From a healthcare delivery perspective, disparities in access to advanced PE treatments remain a significant challenge, particularly in resource-limited settings. While tertiary care centers with dedicated PERTs have demonstrated reduced mortality and shorter hospital stays, many institutions lack the infrastructure to provide real-time multidisciplinary consultations or CDT. Telemedicine-based PERT activation, centralized referral networks, and standardized treatment protocols may help bridge this gap. Additionally, cost-effectiveness analyses of CDT vs systemic anticoagulation will be critical in guiding reimbursement policies and optimizing resource allocation.

Ultimately, the future of PE management will rely on personalized treatment approaches, leveraging risk-adapted strategies to tailor interventions to individual patient profiles. The integration of machine learning algorithms into risk prediction models, combined with real-time physiological monitoring, holds the potential to refine clinical decision-making further. As ongoing trials continue to provide clarity on interventional strategies, the development of international consensus guidelines will be essential to ensure uniformity in PE management across diverse healthcare settings (Figure 1).

Figure 1 Central illustration: Contemporary pulmonary embolism management. Created in BioRender (https://BioRender.com/c33k670). PESI: Pulmonary embolism severity index; sPESI: Simplified pulmonary embolism severity index; NEWS: National Early Warning Score; ESC: European Society of Cardiology; RV: Right ventricle; RV/LV ratio: Right ventricular to left ventricular diameter ratio; TAPSE: Tricuspid annular plane systolic excursion; PASP: Pulmonary artery systolic pressure; PE: Pulmonary embolism; DVT: Deep vein thrombosis; PFO: Patent foramen ovale; CTEPH: Chronic thromboembolic pulmonary hypertension; CDT: Catheter directed treatments; MDT: Multidisciplinary team; PERT: Pulmonary embolism response team; US: Ultrasound.

CONCLUSION

Acute PE remains a major clinical challenge, particularly in identification of apparently stable intermediate-risk patients at risk of hemodynamic compromise and prompt management of high-risk patients. While traditional risk stratification tools have streamlined risk assessment for the majority of patients, gaps persist, particularly in the intermediate-high risk spectrum. Emerging interventional therapies offer promising results in terms of efficacy and safety, but protocols for patient selection and treatment timing are still evolving. PERTs play a crucial role in optimizing care and offering access to novel treatment in selected patients. Addressing immediate and long-term risks is vital for an optimal recovery and warrants a multidisciplinary holistic approach. Future research must focus on validating novel risk stratification tools, refining timing protocols, and evaluating hard clinical endpoints in interventional trials.