ACHAIKI IATRIKI | 2022; 41(4):175–183
Review
Aggeliki Bellou1, Charalampos Lampropoulos2, Fotini Fligou1
1Intensive Care Unit, Department of Anesthesiology and Intensive Care Medicine, University of Patras Medical School, Rio, Patras, Greece
2Intensive Care Unit, Saint Andrew’s General Hospital, Patras, Greece
Received: 05 Apr 2022; Accepted: 22 Jun 2022
Corresponding author: Aggeliki Bellou, Naxou 4, Rio – Patras, 26504, Greece, E-mail: angelabellou@gmail.com
Key words: Venous thromboembolic disease, Pulmonary embolism, Thrombolysis, Low molecular weight heparin (LMWH), Direct oral anticoagulants (DOACs)
Abstract
Pulmonary embolism (PE) is the third most common cause of cardiovascular death worldwide, affecting people of all ages, nationalities, and genders, with an increased incidence in elderly hospitalized patients. PE may present with a spectrum of clinical manifestations ranging from asymptomatic PE to life-threatening PE with hemodynamic instability. Hemodynamic instability is particularly important because it is associated with the risk of premature death. The management of PE has evolved in recent years with the availability of direct oral anticoagulants (DOACs), local thrombolysis, surgical embolectomy, and extracorporeal membrane oxygenation (ECMO). The increasing awareness of healthcare professionals and the development of multidisciplinary PE response teams have also led to significant changes in disease management. In this review we present the latest updates on the management of PE, taking into account the latest ESC / ERS guidelines published in 2019. In addition, we present the most recent publications regarding the occurrence of VTE in COVID-19 patients, the effect of vaccination against SARS CoV-2 on VTE and the most important studies that have been conducted.
INTRODUCTION
Pulmonary embolism (PE) is defined as the blockage of the pulmonary circulation by a substance that has moved from elsewhere in the body through the bloodstream (embolism). In most cases, PE is caused by a thrombus or thrombi that originate in the deep venous system of the lower or (less often) upper extremities. Rarely, PE is the result of fat, amniotic fluid, parasites, or even air embolism into the pulmonary circulation. Such cases are also known as non-thrombotic PE [1]. PE and deep vein thrombosis (DVT) are two different entities of a main disease called venous thromboembolic disease (VTE). VTE is the third most common acute cardiovascular disease and is responsible for causing significant morbidity and mortality, as well as for a significant financial burden on health care systems [2,3]. Although the incidence of PE seems to increase over the years, the mortality rate decreases [4]. This is due to the adherence to the guidelines by clinicians, as well as to the implementation of safer and more effective treatments and non-invasive diagnostic techniques that have emerged in recent years [5].
The prognosis of PE depends on the patient’s hemodynamic compromise, the underlying disease state, and the accurate and prompt diagnosis and treatment. Approximately 34% of patients with PE die suddenly or within a few hours of the acute event, before receiving appropriate treatment, according to epidemiological models [6]. PE is a challenge for clinicians, not only in terms of correct diagnosis, but also regarding appropriate treatment to be applied during the acute phase and long-term follow-up.
The present review summarizes the latest evidence-based recommendations from the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) regarding acute phase and long-term treatment of PE [7]. Acute phase treatment is determined by risk assessment, while long-term treatment is determined by the risk of recurrence.
Assessment of the severity of PE
Assessing the severity of PE is crucial not only for assessing early mortality but also for determining treatment strategy. The severity of PE can be assessed by evaluating the clinical, imaging, and laboratory biological markers associated with right ventricular dysfunction, as well as by evaluating patient’s co-morbidities. Prognostic assessment is important to begin upon suspicion of the disease. There are several clinical scores to determine the severity of PE [8,9]. Most of these are based on clinical findings at the time of diagnosis and risk factors for PE. The Pulmonary Embolism Severity Index (PESI) score is the most frequently used score and has been validated by the ESC / ERS 2019 guidelines [10]. The PESI score evaluates 11 parameters including age, sex, temperature, blood pressure, oxygen saturation, and several co-morbidities. Due to the complexity of the original version, a more simplified version has been developed (Table 1). The main limitation of the PESI score is, as mentioned above, that it includes many variables, which makes this score complex and difficult in everyday clinical practice [11,12].
Hemodynamic instability is of particular importance and reflects the right ventricular compromise, hence the risk of premature death. Hemodynamic instability is a rare phenomenon in acute PE, but when present it requires urgent and appropriate medical care from a multidisciplinary team. Imaging of the right ventricle with either an echocardiogram or CTPA is vital to detect changes in the morphology and function of the right heart [13,14]. These changes are the result of an acute increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR). Biochemical markers that reflect the damage of the myocardium include high circulating levels of highly sensitive troponine I (hs-TNI), brain natriuretic peptide (BNP) and pro-BNP [15,16]. Among the other clinically applicable biomarkers, high serum creatinine and lactic acid levels have been shown to be associated with adverse outcomes in patients with PE [17,18].
Acute phase treatment
During acute phase treatment, the respiratory and hemodynamic stabilization of the patient with PE is of paramount importance.
Ventilation and oxygen therapy: All patients with an oxygen saturation of less than 90% should receive supplemental oxygen therapy. Low arterial oxygen pressure (pO2), which does not respond to conventional oxygen therapy, may be present in patients with right-to-left communication (open foramen ovale) [19]. Particular care should be taken when applying positive end-expiratory pressure to patients with PE, given that positive thoracic pressure may reduce venous return and cardiac output due to right ventricular failure. High flow nasal cannula or non-invasive ventilation with low PEEP should be preferred if the patient can tolerate these methods of ventilation. When mechanical ventilation is necessary, tidal volume (Vt) should be approximately 6ml/kg ideal body weight (IBW), and the end expiratory plateau pressure should be below 30cm H2O.
Right ventricular dysfunction: This condition is the main cause of decreased cardiac output and the leading cause of death in patients at high risk for PE. Fluids should be administered with caution, as they may further reduce cardiac output [20]. Assessment of central venous pressure (CVP) can help assess a patient’s volume status, especially in hypovolemic patients. Vasoconstrictors and inotropes are often necessary, along with other medication [21]. Norepinephrine ameliorates hemodynamic parameters, improving heart contraction and coronary perfusion, without altering pulmonary vascular resistance (PVR). Dobutamine can be used in patients with normal arterial blood pressure, but physicians should be aware that when used without vasoconstrictors it may aggravate or trigger arrhythmias.
Extracorporeal membrane oxygenation (ECMO): The use of venous-arterial ECMO in patients with PE and hemodynamic compromise is controversial and, when necessary, it requires additional intervention, such as surgical embolectomy. Attention should be given to long term application, due to the complications that may occur (hemorrhage) [22]. The efficacy and safety of ECMO depends on the center’s experience and the available expertise [23].
Advanced Life Support (ALS): All healthcare professionals should have the practical skills to manage cardiac arrest and “peri-arrest” problems, according to the European Resuscitation Council (ERC) guidelines [24].
Initial Anticoagulation: Vitamin K antagonists (VKAs) were the mainstay of VTE treatment for more than 50 years. With the introduction of direct oral anticoagulants (DOACs) in the last decade, the therapeutic management of PE has undergone radical changes. However, parenteral anticoagulants (low molecular weight heparin – LMWH, fondaparinux and unfractionated heparin – UFH) still remain the mainstay of treatment for initial anticoagulant therapy in VTE (Table 2).
Anticoagulants: As mentioned above, the treatment of acute phase PE is based on risk assessment. In patients with high-risk PE, it is strongly recommended to start anticoagulant therapy with UFH, including a weight-adjusted bolus dose. In patients with intermediate or low-risk PE, immediate initiation of anticoagulant therapy with LMWH is recommended, when the pre-test probability is intermediate or high. LMWH and fondaparinux are preferred because of lower risk of major hemorrhage or heparin-induced thrombocytopenia (HIT) compared to UFH [25,26]. The use of UFH is limited to patients with hemodynamic compromise who may require reperfusion intervention or to patients with mechanical heart valves and severe renal insufficiency.
An equally fast anticoagulant effect is achieved with VKAs and DOACs. DOACs are molecules that directly inhibit several coagulation factors. Specifically, dabigatran inhibits thrombin, while edoxaban, rivaroxaban and apixaban inhibit factor Xa (Table 3). In several studies apixaban has been shown to be safer for major or clinically relevant non-major bleeding [27]. DOACs are not recommended for patients with severe renal impairment, antiphospholipid syndrome, or patients who are pregnant or breastfeeding. When VKAs are used, concomitant parenteral anticoagulant therapy is recommended for at least 5 days, until INR reaches 2-3 for two consecutive days. Warfarin should be initiated in patients under 60 years old at a dose of 10 mg, while in the elderly at a dose of 5 mg. The dose should then be adjusted over the next 5-7 days, according to INR levels. VKAs have many limitations, especially regarding the need for frequent INR measurements and their pharmacokinetics when taking other medications or foods [28].
Reperfusion treatment: Patients with PE who are hemodynamically unstable should undergo thrombolysis in an intensive care unit. Thrombolysis has been shown to reduce PAP, PVR and RV dilatation. Thrombolysis is most effective when performed within the first 48 hours of the onset of symptoms, although it may be useful in patients with symptom onset for up to 14 days [29]. Thrombolysis is considered successful when the patient’s hemodynamic status and RV dysfunction improve (as shown on the echocardiography 36 hours after thrombolysis) [30]. The impact of thrombolysis has been studied in the Pulmonary Embolism Thrombolysis Study (PEITHO trial) where patients with intermediate high pulmonary embolism underwent thrombolysis. The researchers concluded that although thrombolysis significantly improved RV dysfunction and resulted in reduced mortality from haemodynamic collapse, it increased the risk of severe bleeding [31]. The approved regimens for thrombolysis and contraindications are shown in Table 4 and Table 5, respectively.
Alternatively, patients with high-risk PE or patients with intermediate high PE who worsen may undergo mechanical reperfusion. This is performed by a percutaneous catheter which is directed to the pulmonary arterial bed and fragments and/or aspirates the thrombus. A hybrid method that combines mechanical fragmentation of the thrombus with in situ low dose thrombolysis may also be performed. The overall success rate of percutaneous catheter-directed therapy has been mentioned to be up to 87% [32]. Surgical embolectomy in high-risk PE is performed along with cardiopulmonary bypass and seeks to aspirate fresh thrombi. Recent studies support surgical embolization in combination with ECMO in patients with high-risk PE [33].
Vena cava filters: The placement of a vena cava filter is intended to mechanically prevent thrombi displacement from the lower extremities into the pulmonary circulation. Most vena cava filters are placed percutaneously and can be removed after weeks or months, or left in place for a long time, if necessary. According to the 2019 ESC/ERS guidelines, the indications for placement of a vena cava filter include the following: a) absolute contraindications for anticoagulation, and b) recurrent VTE despite adequate anticoagulation therapy. The PREPIC-2 study showed that vena cava filters compared to standard anticoagulant treatment were associated with a lower risk of PE recurrence, but a significantly higher risk of DVT, and no statistically significant difference in mortality risk [34,35].
Long-term treatment
Long term treatment of VTE aims to: a) be completed without complications, and b) prevent relapses. Most studies on the long-term treatment of VTE include patients with DVT, with or without PE. The risk for recurrence after discontinuation of treatment is associated with the characteristics of the principal event [36]. The recurrence rate after discontinuation of treatment is approximately 2.5% per year for PE associated with transient risk factors, compared to approximately 4.5% per year for PE occurring in the absence of known malignancy, thrombophilia, or other known risk factors [37,38]. The recurrence rate after discontinuation of anticoagulant therapy is similar whether it will stop after 3-6 months or after longer time periods. In addition, it should be borne in mind that although per se anticoagulant therapy reduces the risk of VTE by approximately 90%, it also increases the risk of bleeding (Table 6) [39,40,41].
According to recent guidelines, all patients with VTE should receive anticoagulant therapy for at least 3 months [42]. For patients in whom the first episode of VTE is the result of a major transient or reversible risk factor, discontinuation of anticoagulant therapy at 3 months is recommended [43]. For patients in whom VTE is not associated with a major or reversible risk factor, an indefinite duration of treatment is recommended [44]. VKAs are the treatment of choice in patients with antiphospholipid syndrome [45]. Patients with hereditary thrombophilia, especially those with confirmed protein C, S, antithrombin deficiency or homozygous mutation in prothrombin G20210A, are candidates for indefinite duration of treatment when the main VTE event occurs in the absence of a major transient or reversible risk factor. However, there are no data on the clinical benefits of prolonged anticoagulant therapy in carriers of the G20210A mutation or in patients with heterozygous factor V Leiden. An indefinite duration of treatment is recommended for the first episode of VTE, when there is not known risk factor. In prolonged treatment, DOACs could be used at a reduced dose. In prolonged treatment with DOACs reduced doses may be used [46,47]. Patient compliance, hepatic and renal function should be assessed on a regular basis.
PE during pregnancy
Pulmonary embolism is one of the leading causes of maternal death during pregnancy and treatment must be accurate and immediate [48,49]. According to recent guidelines, any pregnant woman with high or intermediate/low pre-test probability and positive d-dimmer levels should receive LMWH anticoagulant treatment without delay. UFH is not a contraindication during pregnancy, especially when the patient is hemodynamically unstable. UFH should be stopped 6 hours before the delivery [50]. VKAs and DOACs are contraindicated during pregnancy, as they cross the placenta [51]. ESC guidelines recommend thrombolysis in pregnant patients with PE who deteriorate hemodynamically. Health professionals should always keep in mind that PE during pregnancy should be treated by a multidisciplinary team (PERT), including obstetricians.
PE in patients with a malignancy
Patients with a malignancy are at greater risk of developing VTE. In addition, it is widely accepted that patients with a malignancy have a higher recurrence rate of VTE under LMWH (7-9%) compared to patients without malignancy [52]. 2019 ESC / ERS guidelines recommend that patients with a malignancy should receive LMWH for at least 6 months [53,54]. Nowadays, DOACs have been studied in patients with a malignancy. Rivaroxaban and edoxaban may be used in such patients with a malignancy, unless they suffer from gastrointestinal malignancy [55,56]. Patients with a malignancy diagnosed with PE incidentally (for instance, during follow-up CT) should be treated in the same way as symptomatic patients, even if PE involves a single sub-segmental vessel [57]. There is no current data to support the use of vena cava filters as an adjunct to anticoagulant therapy in this group of patients.
PE and COVID-19 infection
Early in the course of COVID-19 disease it was observed that inpatients develop a pro-coagulant state (eg. elevated d-dimers, high levels of von Willebrand and VII factor, platelet activation), leading not only to macrovascular but also microvascular in situ thrombosis [58,59]. This finding has led many researchers to seek the optimal treatment for both thromboprophylaxis and therapeutic anticoagulant regimen in the short and long term. According to the guidelines published in CHEST in February 2022, it is recommended to administer a therapeutic dose (as thromboprophylaxis) of UFH or LMWH (preferably LMWH to reduce staff exposure) in acutely ill patients, that have low bleeding risk. On the other hand, for critically ill patients it is recommended to administer a prophylactic dose, instead of the intermediate or therapeutic dose [60]. Large studies have shown that heparin administered in the early stages of the disease has antiviral and anti-inflammatory action, which are absent in severe ARDS from COVID-19 [61]. In addition, ICU patients were more likely to experience major bleeding, and there was no difference in mortality rates compared with those receiving the therapeutic or intermediate dose of UFH or LMWH [62]. DOACs have no indication for acute thromboprophylaxis or treatment of VTE in those patients [63]. Anticoagulant therapy is not recommended in COVID-19 positive patients who do not require hospitalization [64]. Continuation of heparin is not recommended after discharge [65]. Regarding long term treatment, there are no clear data or large randomized studies. However, it is a fact that the majority of complications occur in the first 30 days. Current guidelines fail to clarify the optimal length of time that anticoagulants will be necessary for patients with COVID-19 and VTE, and it is currently suggested that treatment is similar to standard of care patients.
PE and vaccination against SARS CoV-2
Vaccination against SARS CoV-2 is the most important strategy for ending the pandemic of the disease. Currently in the medical quiver there are several vaccines with different modes of action and different effectiveness [66]. All vaccines are generally safe and effective, and they do not appear to cause more VTE events compared to SARS CoV-2 infection, even in specific patient subgroups [67,68]. There are no robust data to support the exception from vaccination of patients with thrombophilia or to use thromboprophylaxis for a certain time period [69].
CONCLUSIONS
Optimal management of PE involves a multidisciplinary approach and treatment should be individualized. Patient management should start upon disease suspicion using validated risk stratification algorithms. LMWHs remain the treatment of choice for initial anticoagulant therapy. Over the past decade, four DOACs have led to significant changes not only in the chronic treatment of PE but also in the initial anticoagulant therapy. These agents have been tested and proven to be safe for patients with malignancies other than gastrointestinal malignancies. Thrombolysis should be performed in an intensive care unit, with monitoring, and always taking into account absolute contraindications. There is still controversy over the optimal dose of heparin during pregnancy; DOACs are not recommended during pregnancy. Further research is needed to determine the ideal period for anticoagulant therapy based on the risk of recurrence.
Conflict of interest disclosure
None to declare.
Declaration of funding sources
None to declare
Author Contributions
A. Bellou, study conception and design, analysis and interpretation of data; A. Bellou and Ch. Lampropoulos, drafting of manuscript; F. Fligou, critical revision of manuscript.
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