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
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
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
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
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
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 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
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
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
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.
