Summary
Pulmonary embolism can be life threatening and difficult to diagnose as signs and symptoms are not specific. European guidelines recommend stratification of pulmonary embolism by risk of early mortality. Patients with suspected pulmonary embolism should be assessed for clinical probability of pulmonary embolism using a validated risk score. A low or intermediate clinical probability plus a negative high-sensitivity D-dimer test excludes pulmonary embolism. Anticoagulation is indicated in patients with a positive multidetector computed tomography or high-probability lung scan. An important part of the management of patients with pulmonary embolism has traditionally been anticoagulant treatment with parenteral heparins and oral vitamin K antagonists. Although effective, this dual-drug approach is associated with limitations. Direct oral anticoagulants that may overcome some of these problems have been tested in phase III clinical trials for the treatment of venous thromboembolism. Of these, rivaroxaban and apixaban have demonstrated non-inferiority to standard therapy when given as single-drug approaches for venous thromboembolism treatment, and provided significant reductions in major bleeding rates. Dabigatran and edoxaban were non-inferior to standard therapy when given as part of a dual-drug approach after initial parenteral anticoagulation, and reduced clinically relevant bleeding rates. There may be a benefit to extended anticoagulation with direct oral anticoagulants for the prevention of recurrent venous thromboembolism. Registry studies will provide more information on the use of these agents in real-world populations. Accurate diagnosis and risk stratification of patients with pulmonary embolism, together with simplified anticoagulation therapy, is likely to improve outcomes.
Résumé
L’embolie pulmonaire est une pathologie potentiellement létale et est difficile à diagnostiquer. Les signes et les symptômes de l’embolie pulmonaire ne sont pas spécifiques. Les recommandations européennes recommandent de stratifier les malades selon leur risque de mortalité. La probabilité clinique de l’embolie pulmonaire doit être évaluée à l’aide d’un score devant toute suspicion clinique d’embolie pulmonaire. Une probabilité clinique faible ou intermédiaire associée à un taux de D-dimère normal élimine le diagnostic. Le diagnostic est affirmé par l’angioscanner thoracique ou la scintigraphie pulmonaire. Le traitement initial associe traditionnellement une héparinothérapie parentérale et un antagoniste de la vitamine K. Ce traitement est efficace mais comporte certains inconvénients. Des inhibiteurs oraux directs de la coagulation, qui pourraient limiter ces inconvénients, ont été testés dans de grands essais de phase III. Parmi eux, le rivaroxaban et l’apixaban administrés dès l’inclusion ont démontré leur non-infériorité par rapport au traitement standard en termes d’efficacité tout en obtenant une réduction des hémorragies majeures. Le dabigatran et l’edoxaban sont également non inférieurs au traitement standard après un traitement parentéral initial et sont également associés à une réduction des saignements cliniquement significatifs. La prolongation du traitement au-delà de six mois en cas de thrombose non provoquée pourrait être associée à une réduction des récidives. Des études de registres devraient apporter des informations sur l’utilisation de ces nouvelles molécules en situation de soin courant. Un diagnostic rigoureux, associé à une stratification du risque et à un traitement anticoagulant simplifié devraient permettre une amélioration du pronostic de l’embolie pulmonaire.
Introduction
Pulmonary embolism (PE) is a relatively common disease, with an incidence ranging from 60 to 112 per 100,000 inhabitants of the United States , and is the third most common cause of death among patients with cardiovascular diseases . Patients are at particular risk in the acute stage of the disease, with 30-day mortality rates in excess of 15% for PE associated with shock and/or hypotension . PE is difficult to diagnose because of the wide range of presentations of the disease. Among those patients who die of PE, 94% do so before diagnosis . The mainstay of treatment for most patients with PE is anticoagulation, and the risk of death is much reduced in optimally anticoagulated patients. The recurrence rate of venous thromboembolism (VTE) after stopping anticoagulant treatment varies with the cause of the disease and is much higher in patients with unprovoked VTE than in patients with VTE provoked by a major transient risk factor . Duration of anticoagulant treatment is tailored to the risks of VTE recurrence and bleeding for each individual patient .
Treatment of PE has predominantly involved the use of low-molecular-weight heparins (LMWHs), unfractionated heparin or fondaparinux in combination with vitamin K antagonists (VKAs) . However, this dual-drug approach is associated with some limitations, including the need to co-administer the parenteral agent and VKA concurrently for several days at the start of treatment, and the subsequent need for regular coagulation monitoring and dose adjustments during VKA monotherapy. The recently developed direct oral anticoagulants circumvent some of these limitations, and several have completed large phase III clinical trials in the treatment of acute VTE. In Europe, only rivaroxaban is currently approved for the treatment and secondary prevention of deep vein thrombosis (DVT) and PE. In the USA, rivaroxaban and, more recently, dabigatran have been approved for VTE treatment.
This review covers the diagnosis and treatment of PE, focusing on data for direct oral anticoagulants.
Clinical presentations of PE
Most patients with suspected PE present with some degree of chest pain and dyspnoea, a frequent cause of referral to the emergency department. These symptoms are non-specific and can be confused with other differential diagnoses, such as acute coronary syndromes, exacerbation of chronic obstructive pulmonary disease or pneumonia . The most specific symptoms of PE–haemoptysis and calf pain–are encountered in only up to 10% and 42% of patients with PE, respectively . In the most severe cases of PE, patients may present with shock and/or haemodynamic instability . The lack of specific symptoms and the presence of underlying disease in a significant proportion of patients with PE probably explain the significant diagnostic delay observed in some cases.
Risk stratification for suspected PE
Risk stratification is a relatively new concept in the field of PE. The size of the emboli and degree of vessel occlusion do not accurately describe the risk of death of a patient with suspected PE, and the terms ‘massive’ and ‘sub-massive’ are misleading . Therefore, other methods are required to assess mortality risk and inform management decisions. Accordingly, the guidelines of the European Society of Cardiology categorize patients presenting with suspected PE by their predicted risk of early mortality. Patients are divided into high-risk or non-high-risk (which is further divided into intermediate- and low-risk) categories based on the presence of shock, myocardial injury and right ventricular dysfunction detected by echocardiography and cardiac biomarkers . The risk category to which a patient is assigned informs the approach, whether it be emergency thrombolysis or embolectomy (high-risk: > 15% early mortality risk) or further confirmatory diagnostic steps and, if PE is confirmed, management with anticoagulants (non-high-risk: < 1–15% early mortality risk) . Risk stratification also allows for the selection of patients who may be suitable for outpatient anticoagulant treatment .
The Pulmonary Embolism Severity Index is a clinical tool designed to assess the risk of death in patients with PE. According to this, patients with PE can be divided into five groups with different outcomes. The 30-day risk of death in patients belonging to the low-risk categories I and II is usually < 3%, whereas that in patients belonging to the high-risk category V varies between 10% and 25% . A simplified version of the rule, based on six variables that all carry the same weight (one of which is a composite of two original variables), has been shown to have the same sensitivity and specificity as the original . Right ventricular dilatation on echocardiography or computed tomography (CT) pulmonary angiography, and right ventricular dysfunction or injury detected by brain natriuretic peptide and troponin testing, allow further risk stratification of clinically stable patients with PE .
Confirmatory diagnosis in suspected high-risk PE
In patients with suspected high-risk PE, CT pulmonary angiography is the preferred technique to confirm the diagnosis ( Fig. 1 ) . Echocardiography is an alternative if CT pulmonary angiography is unavailable or the patient is too unstable. In haemodynamically unstable patients, acute pulmonary hypertension and right ventricular overload seen on echocardiography may justify a decision for thrombolysis or embolectomy, particularly when other tests cannot be performed ( Fig. 1 ) .
Confirmatory diagnosis in suspected non-high-risk PE
If a diagnosis of non-high-risk PE is suspected, the first step is to assess the clinical probability of PE using a standardized clinical prediction rule ( Fig. 1 ) . According to the result, patients can be divided into three (low, intermediate or high probability of PE) or two (‘PE unlikely’ and ‘PE likely’) groups, each with different probabilities of PE. A negative result from a high-sensitivity D-dimer test in patients with either low–intermediate probability or ‘PE unlikely’ safely excluded PE in about 30% of outpatients presenting to seven Dutch hospitals with suspected PE . In patients with either a high clinical probability or an elevated D-dimer plasma concentration, three options for confirmatory diagnosis are available: CT pulmonary angiography, ventilation–perfusion lung scanning or venous compression ultrasound .
Nowadays, multidetector spiral CT pulmonary angiography is considered the standard option for confirming non-high-risk PE ( Fig. 1 ). Using multidetector spiral CT pulmonary angiography, the rate of recurrent VTE within 3 months after a negative examination has been reported to be as low as 0.3% with or without additional ultrasound, confirming a high sensitivity . Compared with single-detector CT pulmonary angiography and the first generation of multidetector devices, the recent 64-detector systems detect a higher rate of isolated subsegmental PEs, the clinical significance of which has been questioned .
Ventilation–perfusion lung scanning has been used to diagnose PE for many years. A normal ventilation–perfusion lung scan virtually eliminates the diagnosis of PE, but about 50% of examinations are non-diagnostic and do not by themselves allow exclusion or confirmation of the diagnosis of PE . On the other hand, a high-probability scan is strongly correlated with a diagnosis of PE, but further tests may be considered in patients with a low clinical probability risk score .
Compression ultrasound allows diagnosis of DVT in patients with clinically suspected PE, and the finding of a proximal DVT in a patient with clinically suspected PE is accepted as a surrogate for the diagnosis of PE and does not need to be confirmed by an examination of the chest . However, a normal proximal compression ultrasound does not exclude the diagnosis of PE , and only 10% of examinations are positive in patients with suspected PE . Thus, compression ultrasound cannot be considered an efficient diagnostic method for most patients with suspected PE.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
