From acute pulmonary embolism to post-pulmonary embolism sequelae
Functional and hemodynamic implications
Abstract
Summary: Aim of this narrative review is to summarize the functional and hemodynamic implications of acute PE and PE sequelae, namely the post-PE syndrome. Briefly, we will first describe the epidemiology, diagnostic procedures, and therapeutic approaches of acute PE. Then, we will provide a definition of the post-PE syndrome and present the so far accumulated evidence regarding its epidemiology and the implications that arise for further diagnosis and treatment. Lastly, we will explore the most devastating long-term complication of PE, namely chronic thromboembolic pulmonary hypertension (CTEPH), and recent advances in its management.
Abbreviations
| CPET | Cardiopulmonary-exercise testing |
| PE | Pulmonary embolism |
| PH | Pulmonary hypertension |
| V/Q | pulmonary ventilation/perfusion |
Introduction
Acute pulmonary embolism (PE) constitutes one of the most frequent cardiovascular emergencies and the third most frequent cause of cardiovascular mortality. The incidence rate of PE is rising in Europe and the United States, and in 2014, the International Society on Thrombosis and Hemostasis (ISTH) Steering Committee for World Thrombosis Day estimated for PE an incidence rate of 0.15 to 1.15 per 1000 population per year [1]. Clinical research efforts in PE have traditionally been concentrated around the management of the acute event and the avoidance of early complications. The progress that has been made in the management of acute PE is depicted from epidemiological studies of mortality data. Mortality rates both in Europe and in the US have decreased or remained stable during the last two decades despite the rising incidence of PE [2, 3]. However, although the management of the acute event is of particular importance, considering that it usually is life-threatening, survivors of PE may also suffer from long-term sequelae [4].
Over the past years, evidence has been accumulating regarding the long-term complications of PE. These long-term complications can include: signs and symptoms, such as dyspnea, syncope, and chest pain; functional limitations, decreased exercise capacity, and reduced quality of life; echocardiographic abnormalities, mostly involving the right heart; elevated biomarkers, most specifically elevated brain natriuretic peptide levels (BNP); residual thrombi in the pulmonary vasculature; and hemodynamic abnormalities, i.e. elevated mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR). Patients can present with any combination of these aforementioned long-term complications and often the clinical presentation is obscured by co-existing comorbidities, such as chronic cardiopulmonary diseases and cancer, while for other patients mere deconditioning (including an increased body mass index) may be the reason behind the symptoms and functional limitations. Therefore, a definite, precise, and reproducible characterization of a post-PE syndrome is not yet achieved, apart from the most devastating long-term occurrence of PE, the chronic thromboembolic pulmonary hypertension (CTEPH), which is well characterized [5].
Aim of this narrative review is to summarize the functional and hemodynamic implications of acute PE and PE sequelae, namely the post-PE syndrome. Briefly, we will first describe the epidemiology, diagnostic procedures, and therapeutic approaches of acute PE. Then, we will provide a definition of the post-PE syndrome and present the so far accumulated evidence regarding its epidemiology and the implications that arise for further diagnosis and treatment. Lastly, we will explore the most devastating long-term complication of PE, namely chronic thromboembolic pulmonary hypertension (CTEPH), and recent advances in its management.
Acute pulmonary embolism
Epidemiology
After coronary artery disease and stroke, acute PE and deep vein thrombosis (DVT), both subsumed as venous thromboembolism (VTE), are considered globally as one of the most frequent acute cardiovascular syndrome [1]. Annual incidence rates for PE range from 39–115 per 100,000 population; for DVT, incidence rates range from 53–162 per 100,000 population [2, 3, 6]. However, estimated number of unrecorded cases are likely to be substantially higher because silent PE can develop in up to 40%–50% of patients with DVT [7]. Especially in individuals aged ≥80 years the incidence of VTE is almost eight times higher than in the fifth decade of life [1]. Of patients with haemodynamic instability, 65% die suddenly or within a few hours of the acute event, before any therapy can be initiated or take effect [8]. Temporal trend analyses in European, Asian, and North American populations demonstrate that case fatality rates of acute PE decreased over the last years, even if the incidence increased in the same time period [2, 6, 9, 10, 11]. These observations can be explained by an increased use of more effective therapies and interventions, and possibly reflect a better adherence to guidelines [12]. However, in time of COVID-19, recent nationwide studies found a substantially increased PE-related mortality in Germany, Italy and the US, a part of which was also not related to COVID-19 [13, 14, 15].
Diagnostic and therapeutic approaches
Initial risk stratification is immediately mandatory and is based on signs of haemodynamic instability, which indicate a high risk of early death [6]. Thus, initiation of anticoagulation is recommended without delay in patients with high or intermediate clinical probability of PE, while the diagnostic workup is in progress. Those patients need rapid diagnostics. Even if no rapid diagnostics are possible due to several factors, such as cardiopulmonary resuscitation and/or no possibility of transportation to computer tomography pulmonary angiogram (CTPA), the European Society of Cardiology (ESC) guidelines for the diagnosis and management of acute PE underline the importance of a bedside transthoracic echocardiography (TTE) in patients with haemodynamic instability in order to confirm or exclude right ventricular dysfunction (RVD). If acute RVD can be detected, it can be assumed that acute PE is the cause of patient’s haemodynamic decompensation. Alternatively, bedside compression ultrasound (CUS) can be used as a further radiation-free diagnostic approach to detect or exclude proximal DVT and thus consecutive PE. If PE is (in)directly confirmed, in all patients with haemodynamic instability a rescue thrombolytic treatment is recommended if absolute contraindications for systemic thrombolysis are absent. In the case of absolute contraindications, alternative treatment strategies, including catheter-directed low-dose thrombolysis or (percutaneous) thrombectomy, should be taken into consideration [16, 17].
Patients not suffering from haemodynamic instability require further risk stratification after the diagnosis of PE. The 2019 guidelines of the ESC emphasize the importance of risk stratification of the prognostically heterogeneous group of normotensive patients with pulmonary embolism (PE) to define the appropriate treatment strategy [18]. Intermediate-high and intermediate-low risk patients with acute PE should be monitored for a few days and further treatment options are to be re-evaluated in case of decompensation signs. Due to an improvement in risk-adjusted management, but also due to a higher number of patients with smaller emboli diagnosed owing to improved sensitivity of imaging modalities, the prevalence rate of patients with low-risk PE has increased. In this context, significant progress was made in the validation of clinical, biochemical and haemodynamic criteria, which can be used to identify patients with low-risk PE. Since the use of NOACs has facilitated the treatment of low-risk patients with PE without the need for hospitalization, also patients have generally expressed preference for home treatment [19]. In the HoT-PE trial, in which patients were included if the Hestia criteria were fulfilled and no RV dysfunction was present, no PE-related death occurred within the first three months [20]. In a sub-analysis of the Hot-PE trial, although fragile patient population (age >75 years, renal dysfunction [creatinine clearance <50 mL/min], and body mass index <18.5 kg/m2) had higher rate of major bleeding events, all of them occurred after the first 30 days following the diagnosis of acute pulmonary embolism, indicating a safe discharge in mostly all patients with a low-risk PE profile [21].
Late sequelae of pulmonary embolism
Clinical presentation and epidemiology
According to the ISTH Common Data Elements, the term coined “post PE syndrome” encompasses the presence of any of the following after 3 months of adequate therapeutic anticoagulation [22, 23]:
- 1.post-PE functional limitation
- 2.post-PE cardiac impairment
- 3.chronic thromboembolic pulmonary disease (CTEPD) without pulmonary hypertension
- 4.CTEPH
Post-PE functional limitation encompasses new or progressive dyspnea and/or exercise intolerance in the absence of other apparent explanations on diagnostic testing apart from PE. Post-PE cardiac impairment is characterized by incomplete RV echocardiographic recovery, as indicated by an intermediate or high echocardiographic probability of pulmonary hypertension (according to the ESC criteria, this requires the assessment of peak tricuspid regurgitation velocity and/or RV dilatation and hypokinesia plus the presence of exertional dyspnea [24]). CTEPD is defined as the presence of residual thrombi in the pulmonary vasculature along with exertional dyspnea, dead space ventilation and/or pulmonary hypertension during exercise, and in the absence of elevated mean pulmonary artery pressure (mPAP) at rest. Finally, CTEPD with pulmonary hypertension still names as CTEPH and requires ventilation/perfusion scanning for its diagnosis and is characterized by at least one mismatched segmental perfusion defect along with elevated mPAP (≥20 mmHg) and normal pulmonary capillary wedge pressure (PCWP≤15 mmHg) according to the current 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension [23].
Several studies have evaluated the prevalence of echocardiographic abnormalities in the follow-up of acute PE. In a prospective cohort study of patients with sub-massive PE and free of cardiopulmonary disease or any other disabling process, 18/109 (17%) patients showed an abnormal RV on echocardiography (either RV dilatation or hypokinesia) six months after the index event [25]. In a similar prospective cohort of 100 patients without major comorbidities, abnormal RV systolic pressure (>36 mmHg) was found in 4.1% of patients and abnormal tricuspid annular plane systolic excursion (TAPSE <17 mm) in 6.3% of patients [26]. Furthermore, out of 845 PE survivors, 150 (17.8%) showed an intermediate probability of pulmonary hypertension, while 265 (31.4%) showed left ventricular diastolic dysfunction [27]. In another smaller prospective study of 20 patients with sub-massive or massive PE, persistent RV dysfunction and persistent RV dilation was present in 35% of patients at the one-month follow-up with no significant alterations at the 6-month follow-up [28]. Finally, in the Pulmonary Embolism Thrombolysis (PEITHO) trial, 44.1% of patients randomized to tenecteplase and 33.6% of patients who received placebo showed at least one indicator of pulmonary hypertension and/or RV dysfunction on echocardiography at the 6-month follow-up [29]. The incidence of CTEPH did not differ between the two groups, however, the study was clearly underpowered for this outcome; the question whether thrombolysis (or thrombectomy) reduces CTEPH incidence rate is not over. In a post hoc analysis of the same trial, absent recovery of these echocardiographic parameters was associated with the occurrence of CTEPH or post-PE impairment (PPEI) at long-term follow-up (median 3 years after PE the combined endpoint was met in 13.2% of patients) [30].
The literature is lacking large prospective studies with a sufficiently long follow-up period encompassing a set of pre-defined criteria to characterize the full spectrum of the post-PE sequelae (Table I). Recently, a multicenter, prospective, cohort study, the FOllow-Up after aCUte pulmonary embolism (FOCUS) study, which enrolled consecutive unselected patients with confirmed diagnosis of acute symptomatic PE, was completed and contributed to fill, at least in part, this gap in the evidence [24]. The FOCUS study implemented a harmonized, comprehensive 2-year follow-up protocol among expert tertiary centers with the aim to evaluate the incidence of PPEI according to a set of prospectively defined criteria, which would eventually serve as a screening tool for the timely diagnosis of CTEPH. The criteria used in the FOCUS to define PPEI were structured in two main categories: the first category comprised echocardiographic parameters, while the second criterion comprised clinical, functional and laboratory parameters. For the diagnosis of PPEI, the deterioration or the persistence in the worst category of at least one of the first and one of the second criterion was required. Among 1017 patients, the 2-year cumulative incidence of PPEI was estimated at 16%, and patients who fulfilled those criteria were older and presented more frequently with a higher severity PE. Importantly, 15 out of the total 16 patients with a new diagnosis of CTEPH were also diagnosed with PPEI, thus, these criteria helped to narrow the population targeted for an advanced search of CTEPH among all survivors of acute PE. The median time to the diagnosis of CTEPH was 129 days. At least one abnormal echocardiographic parameter was present in 59.5% of patients during follow-up and at least one abnormal clinical, functional, or laboratory parameters was present in 38% of patients during follow-up. PPEI according to the FOCUS criteria was associated with death during follow-up, re-hospitalization for any cause, as well as worse generic and disease-specific quality of life. Of note, especially clinical and functional criteria were mostly connected with readmissions and poor quality of life, even in the absence of echocardiographic abnormalities. Thus, the results of the FOCUS study point to patients, in which appropriate care (exercise rehabilitation, treatment of comorbidity, behavioural education, and modification of risk factors) should be provided to restore their well-being and functional status [24].
Functional and exercise limitation, as well as patient reported outcomes have also been assessed in the recent years by prospective cohort studies. Most notably, the ELOPE study investigated the exercise capacity of a selected population of 100 patients post-PE [26]. At 1 year, 46.5% of patients had decreased exercise capacity as defined by a peak oxygen consumption (VO2) value <80% of the predicted value and male sex, age, high body mass index, and smoking history were predictors of this outcome. Moreover, of 607 consecutive patients diagnosed with PE, 217 (36%) reported exertional dyspnea at 3.6 years after the event, and, similarly with the ELOPE study, cardiopulmonary comorbidity, advanced age, high body mass index, and smoking history were independent predictors [31]. In another study, the percentage of patients reporting dyspnea 6 months after PE was 47%; in the same study the percentage of patients with post-PE impairment (a combination of echocardiographic signs of RV dysfunction and abnormal clinical/laboratory parameters) was 25.3% [32]. Overall, quality of life improves over time in patients with PE [33, 34], also among patients with low-risk PE [35]. The risk stratification at the index event seems to have little value in predicting the course of quality of life over follow-up [34]. However, a fair percentage of patients continues to report complaints up to 12 months after the event [25, 34]. Therefore, the evidence points out that patients with PPEI comprise a spectrum of clinical and functional limitations with or without objective (echocardiographic) signs of cardiac impairment. These limitations have to be therapeutically addressed and in case of cardiac impairment (as the FOCUS study showed) extensive workup for CTEPH diagnosis should be employed.
CTEPH is a rare disease and thus likely to be underdiagnosed. Annual incidence rates of confirmed CTEPH are described heterogeneous with 0.9, 4.0 and 5 per million adults in the western world [36, 37, 38]. In the International CTEPH registry, 74.8% of all patients reported a history of PE [39]. These findings support the concept that CTEPH constitutes a late sequela of PE. Incomplete thrombus resolution followed by vascular remodeling is considered the underlying mechanism responsible for the development of CTEPH after PE [40]. In the FOCUS study, CTEPH was diagnosed in 16 (1.6%) patients; the estimated two-year cumulative incidence was 2.3% (1.2–4.4%), which is in line with previous smaller studies summarized in a recent meta-analysis (Table II) [41]. CTEPH describes symptomatic patients with mismatched perfusion defects after at least 3 months of therapeutic anticoagulation. Pulmonary hypertension in this setting is not only a consequence of large PA obstruction by organized fibrotic clots but can also be present as microvasculopathy [23].
Post pulmonary embolism sequelae
Challenges in diagnostic and treatment implications
Patient reported outcomes, long-term consequences of the disease, disease-specific complications, and treatment-related complications should be recorded in the follow-up of all patients after VTE [42]. In addition, there are several diagnostic tools available to the clinician managing patients after PE, and an algorithm for the screening of patients with post-PE syndrome is described in the 2019 ESC Guidelines for the diagnosis and management of acute PE (Figure 1) [18]. The patient is first evaluated at 3–6 months after PE and therapeutic anticoagulation for the presence of dyspnea and/or functional limitation. In case the patient complains of symptoms and/or presents risk factors for CTEPH (such as previous episodes of PE, imaging findings of the index event suggesting of pre-existing CTEPH, and baseline characteristics such as hypothyroidism and cancer), the echocardiographic examination to determine the probability of pulmonary hypertension is the diagnostic modality of choice due to its availability and the high value and quantity of information that it provides. In case of low probability of pulmonary hypertension, alternative causes of dyspnea should be considered; in case of high probability the next step is to consider a ventilation/perfusion (V/Q) scan of the lungs or new modality such as iodine subtraction mapping, DECT, and MRI perfusion in search for mismatched perfusion defects, after at least 3 months of therapeutic anticoagulation. In case of intermediate probability, the clinician can defer the patient to extra diagnostic testing, including the determination of BNP levels and cardiopulmonary exercise testing (CPET). Normal BNP levels, and specifically for the N-terminal-prohormone of BNP (NT-proBNP), along with normal electrocardiographic characteristics of RV load have been shown to have a high negative predictive value for the diagnosis of CTEPH [43, 44]. In addition, these “rule-out” criteria have been shown to result in a shorter CTEPH diagnostic delay [45]. On the other hand, CPET is a very useful diagnostic modality that can provide valuable information on the pathophysiological origin of the patient’s symptomatology. In particular, CPET enables the identification of anomalies in the respiratory, gas exchange, circulatory, and musculoskeletal systems, as well as the differentiation between particular underlying patterns of activity limitation [46, 47]. A few case-control studies have looked at the function of CPET in the detection of CTEPH, showing that patients with CTEPH have reduced exercise capacity compared to both sedentary controls and people with CTED without pulmonary hypertension [48, 49, 50]. Chronic pulmonary vascular obstruction following PE is associated with deterioration of ventilatory efficiency indicators, which indicate inefficient gas exchange, with CTEPH exhibiting the most pronounced anomalies. Moreover, observational studies have yielded partly conflicting results regarding the prevalence and origin of exercise limitation in the follow-up of acute PE. In the ELOPE study, the authors hypothesized that muscle deconditioning was the most likely source of the exercise restriction, instead of any circulatory or ventilatory dysfunction [26]. On the contrary, in a study by Fernandes et al., 65% of 40 patients with post-PE dyspnea displayed a higher physiological dead space fraction at the AT and/or a lower stroke volume reserve, implying that the majority of these patients are likely to have physiologic cardiopulmonary limitations rather than just deconditioning [51]. Nevertheless, the usefulness of the CPET in the evaluation of post-PE dyspnea is high and this is delineated in a recently published position paper on the optimal follow-up after acute pulmonary embolism by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function [52]. Along the assessment of the probability of CTEPH, risk factors such as permanent intravascular devices, inflammatory bowel diseases, essential thrombocythaemia, polycythaemia vera, splenectomy, antiphospholipid syndrome, high-dose thyroid hormone replacement, and malignancy should be taken into consideration as well [5, 53].
Patients diagnosed with CTEPH or with a strong suspicion of CTEPH should be referred to an expert pulmonary hypertension clinic for further multidisciplinary diagnostic and treatment such as pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and/or targeted pulmonary hypertension medical treatment [5]. Surgical PEA is the treatment of choice for operable patients and its use increased in the past years [54]. Even if post-operative PH occurred in one fourth of all cases, long-term outcomes after PEA surgery are excellent regarding survival rates and quality of life [55, 56, 57]. If patients are not suitable for PEA surgery, medical treatment and/or balloon pulmonary angioplasty have become an established treatment. Operability should be evaluated by a multidisciplinary team, which should fulfil criteria for a PH centre. Such an experienced team should consist of consisting of a PEA surgeon, BPA interventionist, PH specialist, and thoracic radiologist, trained in high-volume PEA and/or BPA centres [23].
However, the majority of patients with post-PE syndrome will not fulfill the criteria for CTEPH or even CTEPD diagnosis. For these patients, who actually comprise the majority of patients with post-PE syndrome, alternative treatment modalities should be considered if the diagnostic testing does not reveal alternative causes of dyspnea and functional limitation. An attractive option may be cardiopulmonary rehabilitation [58]. Although chronic pulmonary obstructive disease provides the majority of the evidence in the field of pulmonary rehabilitation, some research on post-PE follow-up has been already performed. Rehabilitation studies in CTEPH have shown that it is feasible even after PEA and improves exercise capacity, haemodynamics, and RV function [59, 60, 61]. Research on post-PE rehabilitation has so far shown variable findings: A small randomized controlled study of 140 unselected PE patients found no difference between standard care and physiotherapist-guided home exercise planning for increasing physical activity [62]. In contrast, two single-arm cohort studies showed that patients with post-pulmonary embolism dyspnea could benefit from an outpatient pulmonary rehabilitation program in terms of their physical functional status (measured by meters walked during a 6-minute walking test) and quality of life [63, 64]. Certainly, there is currently a paucity of solid randomized data on the effectiveness of pulmonary rehabilitation in improving physical capacity in patients with persistent dyspnea or functional impairment during the follow-up of PE. Assuming that cardiopulmonary rehabilitation will concern 10–20% of symptomatic, without major comorbidities, patients after PE, the societal burden of such an intervention may be significant. Future studies should assess the cost effectiveness of this approach, considering that it may reduce loss of productivity, and how reimbursements may be affected should be based on the future evidence.
Conclusions
Acute PE is a life-threatening disease with evolving reperfusion strategies. However, beyond the acute phase of PE, the long-term course may be complicated by persisting and progressive hemodynamic and functional impairment with CTEPH at the far end of the severity spectrum (Table III). In recent years, significant progress was made in the validation of clinical, biochemical and haemodynamic criteria, which can be used to identify patients with post-pulmonary embolism sequelae. Further studies are needed to elucidate and develop appropriate ambulatory care protocols with the aim to support patients with persisting symptoms and limitation in order to improve physical capacity and quality of life.
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