Post–Pulmonary Embolism Syndrome: An Update Based on the Revised AWMF-S2k Guideline

Abstract

In survivors of acute pulmonary embolism (PE), the post-PE syndrome (PPES) may occur. In PPES, patients typically present with persisting or progressive dyspnea on exertion despite 3 months of therapeutic anticoagulation. Therefore, a structured follow-up is warranted to identify patients with chronic thromboembolic pulmonary disease (CTEPD) with normal pulmonary pressure or chronic thromboembolic pulmonary hypertension (CTEPH). Both are currently understood as a dual vasculopathy, that is, secondary arterio- and arteriolopathy, affecting the large and medium-sized pulmonary arteries as well as the peripheral vessels (diameter < 50 µm). The follow-up algorithm after acute PE commences with identification of clinical symptoms and risk factors for CTEPH. If indicated, a stepwise performance of echocardiography, ventilation–perfusion scan (or alternative imaging), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level, cardiopulmonary exercise testing, and pulmonary artery catheterization with angiography should follow. CTEPH patients should be treated in a multidisciplinary center with adequate experience in the complex therapeutic options, comprising pulmonary endarterectomy, balloon pulmonary angioplasty, and pharmacological interventions.

Keywords

pulmonary embolism - chronic thromboembolic pulmonary hypertension - chronic thromboembolic pulmonary disease - pulmonary endarterectomy - balloon pulmonary angioplasty

In patients with acute pulmonary embolism (PE), symptoms may not resolve completely despite optimal diagnostic and therapeutic management. Therefore, a structured follow-up strategy is required to identify the presence of a post–pulmonary embolism syndrome (PPES)[31].

The PPES is a well-known complication after acute PE characterized by new or increasing dyspnea and/or reduced physical exercise or mental capacity. According to the definition provided in the European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension,[1] [2] the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) is based on findings obtained after at least 3 months of effective anticoagulation in order to differentiate this condition from “subacute” PE. These findings comprise mean pulmonary artery pressure (mPAP) > 20 mm Hg with pulmonary vascular resistance (PVR) > 2 Wood units, mismatched perfusion defects on lung scan, and specific diagnostic signs for CTEPH identified by multidetector computer tomography pulmonary angiography (CTPA), magnet resonance imaging (MRI), or conventional pulmonary angiography, including ringlike stenoses, webs/slits, and chronic total occlusions (pouch lesions or tapered lesions).[2] [3] [4]

According to a recent review, intravascular alterations following symptomatic acute PE are detectable in up to 50% of patients.[5]

Recently, the prospective Follow-Up after Acute Pulmonary Embolism (FOCUS) - a Prospective Observational Multicenter Cohort Study found symptoms in 16% of patients within the first 2 years after symptomatic acute PE.[6] However, only a small proportion of these patients will develop a CTEPH.[2] [3] The incidence of CTEPH is 0.1 to 11.8% in patients with symptomatic venous thromboembolism, corresponding to a 2-year incidence of 2.8 to 8%.

According to the authors of a meta-analysis including 16 studies, CTEPH occurs in 3% of survivors of acute PE, in most cases within the first 2 years, rarely within 7 years, after the acute event.[7]

Prognosis is reduced in CTEPH, since the 5-year survival is 60%, and only 30% in patients with mPAP greater than 40 mm Hg.[8]

Recently, the term chronic thromboembolic pulmonary disease (CTEPD) has been coined for symptomatic patients without pulmonary hypertension at rest, but with a ventilation–perfusion mismatch or organized intravascular thrombotic residual material despite 3 months of therapeutic anticoagulation.[9] To date, it is unclear whether CTEPD is an independent condition or rather a preliminary state that may later develop into CTEPH.

In patients with CTEPD, symptoms are often nonspecific, including dyspnea and exercise intolerance. Frequently, muscular deconditioning or comorbidities have to be identified as independent factors. Therefore, it is crucial to perform timely functional and imaging evaluation in symptomatic patients and to initiate adequate treatment.[1] [2] [10]

Chronic Thromboembolic Pulmonary Hypertension

Currently, CTEPH is understood as a dual vasculopathy (secondary arterio- and arteriolopathy) affecting the large and medium-sized pulmonary arteries as well as the peripheral vessels (diameter < 500 µm). It has been summarized as a complex pathophysiology due to vascular derangements in both the elastic and resistive pulmonary arteries.[10] In contrast to acute PE, a linear correlation between the extent of mechanical obstruction on imaging and the severity of PVR is not found. In CTEPH, there is a progressive pulmonary vascular remodeling that develops in both occluded and nonoccluded small pulmonary arteries.[10]

The diagnosis of CTEPH is based on a ventilation–perfusion mismatch, specific findings in CT, MRI, or conventional pulmonary angiography, and—traditionally—an mPAP of ≥25 mm Hg at rest with a left ventricular end diastolic pressure (LVEDP) ≤15 mm Hg following ≥3 months of therapeutic anticoagulation.[11] In the recent ESC/ERS guidelines, CTEPH is defined hemodynamically by an mPAP greater than 20 mm Hg and a PVR greater than 2 Wood units at rest and is classified in group 4 (PH associated with pulmonary arterial obstruction).[1]

Follow-Up after Acute Pulmonary Embolism and Screening for CTEPH

A structured follow-up is mandatory in patients after acute PE, and this should enable prompt diagnosis and therapy as described by Delcroix et al[2] (see [Fig. 1]). In CTEPH patients, earlier diagnosis may improve prognosis. Therefore, patients with acute PE and risk factors for CTEPH ([Tables 1] and [2]) or with radiological findings suggesting CTEPH ([Table 3]) need to be identified by accurate assessment of the CTPA images used to diagnose PE, individual risk factors for CTEPH, and symptoms of functional limitations and/or right heart failure in the course of PE.[2]

Fig. 1 Algorithm for follow-up after acute pulmonary embolism and screening for chronic thromboembolic pulmonary hypertension (CTEPH). For CTEPH score, see [Table 1].[31] Abbreviations: CT, computed tomography; CT-PA computer tomography - pulmonary artery, CTEPD, chronic thromboembolic pulmonary disease, CTEPH, chronic thromboembolic pulmonary hypertension; MRA, magnetic resonance imaging angiography, NT-proBNP, N-terminal prohormone of brain natriuretic peptide, PE, pulmonary embolism; PH, pulmonary hypertension, sPAP systolic pulmonary artery pressure, TTE, transthoracic echocardiography, V/Q-scintigraphy, ventilation-perfusion scintigraphy.

Table 1 CTEPH prediction score

Unprovoked PE	+6 points
Known hypothyroidism	+3 points
Symptom onset >2 wk before PE diagnosis	+3 points
Right ventricular dysfunction on CT or TTE	+2 points
Known diabetes mellitus	−3 points
Thrombolytic therapy or embolectomy for the acute PE event	−3 points

Abbreviations: CT, computed tomography; CTEPH, chronic thromboembolic pulmonary hypertension; PE, pulmonary embolism; TTE, transthoracic echocardiography.

Note: Low risk: ≤6 points. High risk: >6 points.

Table 2 Risk factors and predisposing conditions for CTEPH

Findings related to the acute PE event[a]	Concomitant chronic diseases and conditions predisposing to CTEPH
Previous episodes of PE or DVT	Ventriculoatrial shunts
Large pulmonary arterial thrombi on CTPA	Infected chronic i.v. lines or pacemakers
Echocardiographic signs of PH/RV dysfunction	History of splenectomy
CTPA findings suggestive of CTEPD[b]	Thrombophilic disorders, particularly antiphospholipid antibody syndrome and high coagulation factor VIII levels
	Non-O blood group
	Hypothyroidism treated with thyroid hormones
	History of (active) cancer
	Myeloproliferative disorders
	Inflammatory bowel disease
	Chronic osteomyelitis

Abbreviations: CTEPD, chronic thromboembolic pulmonary disease; CTEPH, chronic thromboembolic pulmonary hypertension; CTPA, computed tomography pulmonary angiography; DVT, deep vein thrombosis; PE, pulmonary embolism; PH, pulmonary hypertension; RV, right ventricular.

Source: Reproduced from Konstantinides and Meyer.[11]

^a Obtained at PE diagnosis.

^b Documented at PE diagnosis or at 3 to 6 months of follow-up.

Table 3 Findings of preexisting CTEPH on computed tomography pulmonary angiography

Direct vascular signs

• Eccentric wall-adherent filling defect(s), which may calcify; different from the central filling defects within a distended lumen, which are the hallmark of acute PE

• Abrupt tapering and truncation

• Complete occlusion and pouch defects

• Intimal irregularity

• Linear intraluminal filling defects (intravascular webs and bands)

• Stenosis and post-stenotic dilatation

• Vascular tortuosity

Indirect vascular signs

• Significant RV hypertrophy, RA dilatation

• Pericardial effusion

• Dilatation of pulmonary artery (>29 mm in men and >27 mm in women) and/or calcifications of pulmonary artery

• Systemic collateral arterial supply (bronchial arterial collaterals toward pulmonary postobstructive vessels)

Parenchymal changes

• Mosaic attenuation of the lung parenchyma resulting in geographical variation in perfusion

Abbreviations: CTEPH, chronic thromboembolic pulmonary hypertension; PE, pulmonary embolism; RA, right atrial; RV, right ventricular.

Source: Reproduced from Konstantinides and Meyer[11] and Klok et al.[12]

Echocardiography

Although a routine echocardiography in all patients after acute PE is not recommended, it is the mainstay for follow-up in selected patients with new or persisting exertional dyspnea and reduced exercise capacity, and in patients with risk factors for CTEPH.[2] Typical findings indicating pulmonary hypertension ([Table 4]) have been described in the recent ESC/ERS guidelines.[1]

Table 4 Additional echocardiographic signs suggestive of pulmonary hypertension (PH)[a]

A: the ventricles

• RV/LV basal diameter/area ratio >1.0

• Flattening of the interventricular septum (LVEI >1.1 in systole and/or diastole)

• TAPSE/sPAP ratio <0.55 mm/mmHg

B: 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

C: inferior vena cava and RA

• IVC diameter >21 mm with decreased inspiratory collapse (<50% with a sniff or <20% with quiet inspiration)

• RA area (end systole) >18 cm2

Abbreviations: AR, aortic root; IVC, inferior vena cava; LV, left ventricle; LVEI, left ventricle eccentricity index; PA, pulmonary artery; RA, right atrium; RV, right ventricle; RVOT AT, right ventricular outflow tract acceleration time; sPAP, systolic pulmonary arterial pressure; TAPSE, tricuspid annular plane systolic excursion; TRV, tricuspid regurgitation velocity.

^a Signs contributing to assessing the probability of PH in addition to tricuspid regurgitation velocity. Signs from at least two categories (A/B/C) must be present to alter the level of echocardiographic probability of PH.

Cardiopulmonary Exercise Testing

Cardiopulmonary exercise testing (CPET) is a versatile diagnostic instrument to clarify the differential diagnosis of dyspnoea in patients with suspected CTEPH or CTEPD.[3] [13] [14] The typical findings reflect reduced exercise capacity, reduced cardiac output reserve (O₂ pulse at ventilatory threshold 1 [VT1]/O₂ pulse at rest: <28% or <2.37, respectively) or other hemodynamic alterations and increased dead space ventilation due to ventilation–perfusion mismatch (Vd/Vt ≥ 0.38 at rest and ≥0.27 at VT1).[15]

Imaging Techniques

Detailed analysis of the initial radiological material obtained at the time of the index event might provide additional information with respect to the development of CTEPH and should therefore be included in the standardized follow-up. Typical findings can permit a valid diagnosis of CTEPH (specificity 96%, sensitivity 72%).[16] [17] [18] In experienced hands, pulmonary angiography by CT or magnetic resonance tomography (MRT) is adequate for the follow-up of acute PE patients. However, a CTPA alone cannot reliably exclude the presence of CTEPH and should be supplemented by V/Q scintigraphy.[2] [10] Consequently, patients with positive noninvasive test results (standardized algorithm) should undergo catheter-based pulmonary angiography and right heart catheterization, preferably in a CTEPH or PH center, where state-of-the-art therapeutic options including surgical, interventional, and pharmacological treatment are available (see section on CTEPH treatment).[10]

Recommendations for the Diagnostic Algorithm after Pulmonary Embolism

In patients with acute PE, a structured follow-up after 3 (to 6) months with evaluation of symptoms indicative of CTEPH is mandatory. In the presence of symptoms or risk factors, echocardiography is indicated. If echocardiography points toward CTEPH, further investigations including cardiopulmonary exercise testing, ventilation–perfusion scan, CT or MRT with pulmonary angiography, and right heart catheter with angiography are necessary to diagnose or exclude CTEPH.

Treatment of Chronic Thromboembolic Pulmonary Hypertension

The modern management of CTEPH patients is complex and needs dedicated and experienced teams of medical specialists and nursing staff.[10] [19] Therefore, it has been recommended to refer CTEPH patients for comprehensive invasive diagnostic evaluation and interdisciplinary conference decision on treatment options to experienced centers.[2] [11]

In PH centers, members of a multidisciplinary team work according to standardized procedures (e.g., conferences, clinical pathways). They have access to clinical studies and research facilities and follow more than 50 patients with pulmonary arterial hypertension (PAH) or CTEPH and receive more than two new referrals per month with documented PAH or CTEPH.[1] Additionally, CTEPH centers are specialized “to optimize” patients' outcomes, fulfil criteria for a PH center and have a multidisciplinary CTEPH team consisting of a pulmonary endarterectomy (PEA) surgeon, balloon pulmonary angioplasty (BPA) interventionalist, PH specialist, and thoracic radiologist, trained in high-volume PEA and/or BPA centers. The team should meet regularly to review new referrals and posttreatment follow-up cases. Ideally, CTEPH centers should have high-volume PEA activities (>50/y) and BPAs (>30 patients/y or >100 procedures/y), as these figures have been associated with better outcome (30-day mortality <3%, 3-year survival >90%). These CTEPH centers should also manage medically treated patients.[1] [20] [21]

In the therapy algorithm for CTEPH aptients (see [Fig. 2]), anticoagulation and either surgical or endovascular interventions for reopening pulmonary vessels are indicated, when technically feasible. Depending on the location of the obstructions (proximal [segment level], intermediate or distal [arteries of 2–5 mm diameter]) and the experience of the performing center, either PEA or BPA is preferred. If treatment focuses on pulmonary microvasculopathy, vasodilation by pharmacotherapy is indicated ([Fig. 2]).

Fig. 2 Therapy algorithm in CTEPH. BPA, pulmonary balloon angioplasty; CTEPH, chronic thromboembolic pulmonary hypertension; PEA, pulmonary endarterectomy.

Anticoagulation

In all CTEPH patients, lifelong therapeutic dose anticoagulation is indicated. Anticoagulation is still indicated after patients have undergone successful PEA and/or BPA. So far, vitamin K antagonists (VKAs) are considered the first-line therapy in CTEPH, especially in patients with antiphospholipid syndrome.[22] Although being increasingly used, the role of DOAC is not completely defined. As far as comparative data are available, new thromboembolic events occurred more often in CTEPH patients treated by DOACs as compared to VKA, although head-to-head comparisons are lacking.[22] [23] If a DOAC regimen is considered in CTEPH, low-dose anticoagulant therapy with apixaban or rivaroxaban, which is an option in secondary prevention after uncomplicated PE or deep vein thrombosis, is not recommended.[10]

Surgical Treatment by Pulmonary Endarterectomy

Surgical treatment by PEA has been established by dedicated surgical centers as the treatment of choice in all CTEPH patients with fibrotic obstructing lesions in pulmonary arteries, which can be accessed by surgery.[2] [10] [11] The discussion and decision within a multidisciplinary conference in a CTEPH center (or at least PH center) improves selection and perioperative outcome of PEA. Even older patients (>70 years) or those with high PVR (>12.5 Wood units) undergoing PEA do benefit in experienced centers.[24] Pulmonary hemodynamics improve shortly after PEA, whereas recovery of clinical status and exercise tolerance may be delayed by 3 to 12 months. Some degree of PH persists in up to 50% of PEA cases.[2] Within the first 12 months after surgery, regular 6-minute walk test (6-MWT) or cardiopulmonary exercise testing, thoracic imaging, and right heart catheterization will identify symptomatic patients in whom percutaneous balloon angioplasty (PBA) or pharmacological treatment (riociguat) is indicated.

Balloon Pulmonary Angioplasty

In patients with obstructions in peripheral pulmonary arteries, or with persisting pulmonary hypertension after PEA, the indication for BPA should be evaluated and the procedure should be performed in a specialized center.[1] [2] [20] In patients with a given BPA indication, it should be discussed whether pharmacological PH treatment with riociguat is initiated prior to BPA and in between procedures, since it has been shown to reduce the risk of reperfusion damage.[10] [25]

Pharmacological Treatment of Pulmonary Hypertension

It is important to understand CTEPH as a dual vasculopathy that may involve both proximal and peripheral pulmonary vessels ([Fig. 3]). Accordingly, the different treatment options are applied separately or in combination ([Fig. 3]). In symptomatic CTEPD patients without an indication for PEA, or with persisting pulmonary hypertension after PEA, riociguat orally and treprostinil subcutaneously are approved in Germany. Other medications used for PAH have been evaluated and are frequently used off-label.[2]

Fig. 3 Therapeutic modalities addressing different pulmonary vascular zones in patients with CTEPH. BPA, balloon pulmonary angioplasty; CTEPH, chronic thromboembolic pulmonary hypertension; PA, pulmonary artery; PEA, pulmonary endarterectomy. ( Reproduced with permission of © European Society of Cardiology & European Respiratory Society 2024: European Respiratory Journal 61 (1) 2200879; DOI: 10.1183/13993003.00879-2022 Published 6 January 2023.)

Rehabilitation

Recent studies, including 129 CTEPH patients on stable dose pharmacologic treatment from 11 rehabilitation clinics, documented the feasibility, safety, and effectiveness of a standardized inpatient or outpatient rehabilitation program.[26] Moreover, following PEA or BPA, an intensive rehabilitation program is already regarded as standard management.[2] [27]

Chronic Thromboembolic Pulmonary Disease

Chronic thromboembolic pulmonary disease (CTEPD) is defined as chronic obstruction of the pulmonary vasculature. Although mPAP is normal at rest (<20 mm Hg), CTEPD patients are limited by exercise intolerance, which can partially be attributed to increased dead space ventilation and exercise-induced pulmonary hypertension (increased mPAP/cardiac output slope during exercise, i.e., >3 mm Hg/L/min).[1] [28]

Diagnosing CTEPD requires the exclusion of other possible differential diagnoses, including restrictive or obstructive ventilatory dysfunction, deconditioning, dysfunctional breathing, and left ventricular dysfunction.

During exercise, right ventricular contractile reserve and ejection fraction are reduced.[29] Moreover, in CTEPD patients, dead space ventilation might be increased at rest and persist during exercise.[29] This can easily be identified by cardiopulmonary exercise testing when ventilatory inefficiency (increased VE/VCO₂ slope) or reduced end-tidal CO₂ partial pressure is observed.[29] [30] In addition, adequate imaging, for example, dual-energy CTPA, is crucial to identify a mosaic perfusion pattern. The optimal treatment for CTEPD patients is still a matter of discussion. Since CTEPD patients might progress into CTEPH patients, regular reevaluation is recommended.

Conclusion

A structured follow-up after acute PE is crucial to identify patients with persistent or progressive symptoms, mainly dyspnea on exertion. Applying a stepwise diagnostic approach following the proposed algorithm allows efficient and prompt diagnosis of CTEPH. CTEPH patients should be treated in multidisciplinary centers with adequate experience in the complex therapeutic options, including surgical, vascular, and pharmacological interventions.

Conflict of Interest

FJM has received Honoraria for lectures from Jansen-Cilag, Boehringer and Novartis.

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Publication History

Received: 16 September 2023

Accepted: 13 December 2023

Article published online:
26 March 2024