David Ho, DO1
Bob Smouse, MD2
1University of Illinois College of Medicine–Peoria, Peoria, IL; 2Central Illinois Radiological Associates, Peoria, IL
Correspondence: David Ho, DO,
University of Illinois College of Medicine–Peoria,
530 NE Glen Oak Avenue,
Peoria, IL 61637.
Acute pulmonary embolism can be difficult to diagnose on physical examination due to its widely variable presentation, ranging from asymptomatic to cardiovascular shock. Similarly, mortality is also variable, with high risk of death in patients with shock symptoms and low risk of death in patients without shock. Therefore, rapid assessment and accurate risk stratification is important to determine treatment and ensure quality care. This article reviews the literature and provides updates on classification systems and risk stratification, tools used in the diagnosis, and emerging treatment methods for pulmonary embolism.
pulmonary embolism; respiratory tract diseases; lung diseases; embolism and thrombosis; venous thrombosis
Acute pulmonary embolism (PE) is part of a spectrum of disease known as venous thromboembolism (VTE). Venous thromboembolism begins as thrombosis within the deep veins of either the upper or lower extremities and can embolize, traveling proximally, ultimately lodging in the pulmonary arteries. Pulmonary embolism is a significant cause of mortality and morbidity. Due to its variable initial presentation, many cases of PE go unrecognized, and thus the true incidence of PE is difficult to estimate. Community-based studies have previously estimated the annual incidence of pulmonary embolism to be 60 to 69 cases per 100 000 people and that of VTE to be 117 to 183 cases per 100 000.1,2 However, these studies preceded the widespread use of CT pulmonary angiography (CTPA) in the diagnosis of PE.
Studies published by DeMonaco et al3 in 2008 and Wiener et al4 in 2011 both demonstrated significant increases in the incidence of PE while severity of illness and mortality decreased over the same time periods. DeMonaco et al used data from the Pennsylvania Health Care Cost Containment Council from 1997 to 2001 and found that the incidence of PE increased from 47 to 63 per 100 000, with the proportion undergoing CTPA increasing from 23.23% to 45.18%.3 During the same time period, mortality in patients with PE decreased from 12.8% to 11.1%, and severity of illness shifted from the higher or more severe scores to the lower or less severe scores.3 The increased incidence and concomitant decrease in mortality and severity of illness was thought to be due to earlier detection of PE.
More recently, Wiener et al4 used data from the Nationwide Inpatient Sample spanning time periods before and after the widespread use of CTPA in the diagnosis of PE. They found that between 1993 and 1998, before the era of CTPA, the incidence of PE did not significantly change, rising from 58.8 to 62.3 per 100 000. After 1998, the incidence of PE increased significantly from 62.3 to 112.3 per 100 000. Similarly, mortality was measured over these time periods, and there was an 8% decrease in mortality from 1993 to 1998 before CTPA and a 3% decrease after CTPA. The authors postulated that overdiagnosis explains this rapid rise in incidence of PE without a significant change in mortality from PE since the widespread use of CTPA for diagnosis. “Much of the increased incidence in PE consists of cases that are clinically unimportant, cases that would not have been fatal if left undiagnosed and untreated.”4 Overdiagnosis is important to recognize because treatment of PE has its own risks, especially in patients in whom PE can be deemed clinically unimportant. Wiener et al conclude their article by stating that “better technology allows us to diagnose more emboli, but to minimize harms of overdiagnosis we must learn which ones matter.”
Materials and Methods
A search of PubMed, Google Scholar, and the National Guideline Clearinghouse was performed to find articles pertaining to PE and its epidemiology, pathophysiology, classification, diagnosis, and treatment. The search terms incidence, epidemiology, diagnosis, laboratory tests, imaging, classification, pretest probability, treatment, and pregnancy were used in conjunction with the primary search term acute pulmonary embolism. For topics concerning epidemiology and pathophysiology, articles from all time periods were included. For topics pertaining to classification, risk stratification, diagnosis, diagnostic tests, and treatment recommendations, all articles were reviewed, but evidence and recommendations from articles within the past 5 years were preferred. We included studies from peer-reviewed sources, a majority of which were meta-analyses or retrospective studies. We also hand-searched bibliographies of retrieved papers for additional references as appropriate.
Venous thromboembolism is a dynamic disease, and understanding its pathogenesis has implications for prevention as well as for treatment. Rudolf Virchow,5 a pathologist credited with describing the pathophysiology of VTE, is often quoted as describing emboli as “the detachment of larger or smaller fragments from the end of the softening thrombus which are carried along by the current of blood and driven into remote vessels. This gives rise to the very frequent process on which I have bestowed the name of Embolia.” Using autopsy cases, Virchow showed that the clot in the pulmonary arteries came from a distal source instead of de novo in the lungs, as was previously thought.
The often-cited Virchow’s triad describes the factors contributing to the formation of venous thrombi consisting of hypercoagulability, stasis, and endothelial injury. Though named after Virchow, the elements of the triad were neither proposed by Virchow nor did he ever suggest that a triad would describe the pathogenesis of VTE. It would be almost a hundred years after Virchow’s death before a consensus was reached proposing that thrombosis resulted from alterations in blood flow, vascular endothelial injury, or alterations in the constitution of blood. Still, the modern understanding of factors leading to thromboembolism is similar to descriptions provided by Virchow. Its nebulous origins notwithstanding, Virchow’s triad remains a useful concept for clinicians and pathologists in understanding the contributing factors to thromboembolism.6 Many of the known risk factors for VTE and PE can be categorized into ≥ 1 of the factors of Virchow’s triad (Table 1).
Venous stasis is the prominent contributing factor to the formation of deep venous thrombosis (DVT). Thrombus formation occurs in venous valve pockets due to a combination of slow flow and endothelial inflammation caused by blood flow turbulence within these pockets.7,8 These inherent factors, combined with conditions leading to prolonged immobility, as can occur in paralysis, long car or plane rides, recent surgery, limb trauma, myocardial infarction, or stroke, can increase the risk of VTE. Obesity may also lead to increased VTE, although the mechanism for this association is unknown.
Advanced age, as with many other disease processes, increases the risk of thrombus formation. Hypercoagulable states, whether inherited or acquired, predispose patients to clotting. Inherited hypercoagulable states include factor V Leiden mutation, protein C or S deficiency, antithrombin deficiency, and a prothrombin gene mutation. The most commonly encountered acquired hypercoagulable states occur with cancer, recent surgery, pregnancy, estrogen or oral contraceptive therapy, lupus anticoagulant or antiphospholipid antibodies, polycythemia rubra vera, dysfibrinogenemia, and hyperhomocystinemia. It should be noted that the incidence of VTE in patients with a clotting disorder or thrombophilia is low,9 and as a result, routine testing for thrombophilia is not recommended, as it does not alter treatment in most cases.10 Common tests used in the workup of hypercoagulable states are found in Table 2.11
Once DVT forms in upper or lower extremity veins, a piece of the thrombus can break off and can flow through the superior or inferior vena cava, respectively, through the right heart, and lodge in the pulmonary arteries; it is then referred to as pulmonary embolism. The severity of symptoms correlates with the degree of occlusion of the pulmonary arterial vasculature, with the largest and most life-threatening emboli lodging in the central pulmonary arteries. This manifests as right heart strain or dysfunction. The obstructive burden leads to increased pulmonary arterial pressures and right ventricular (RV) afterload. This increase in afterload results in dilation of the right ventricle and bowing of the interventricular septum toward the left ventricle. In severe cases, this bowing can lead to reduction in left ventricular (LV) preload, and it decreases systemic and coronary circulation, which begins a downward spiral leading to cardiogenic shock. Mortality in those patients with systemic hypotension or cardiogenic shock can be as high as 60% to 65%.12,13
Upper Extremity DVT Causing PE
In the discussion of VTE, upper extremity (UE) DVT is considered a relatively rare condition when compared with lower extremity DVT. However, catheter-related UE DVT is a rising issue given the fact that the use of intravenous lines for acute and long-term use is increasing.14 Studies have found that central catheters may account for 12% to 35% of all diagnosed UE DVTs,15,16 with larger diameter peripherally inserted central catheters and malignancy increasing the risk for DVT.16 Prior studies have found that PE is actually not a rare complication of UE DVT, ranging from 6% to 20%.17–20 In a study by Muñoz et al21 using data from the Registro Informatizado de Enfermedad TromboEmbólica (RIETE), the computerized registry of patients with VTE, patients with UE DVT presented with PE in 9% of cases.
The latest American College of Chest Physicians guidelines recommend starting parenteral low molecular weight heparin or fondaparinux in the acute phase of UE DVT occurring in the axillary or more proximal veins.22 In those patients whose UE DVT is associated with a central venous catheter, recommendations are to maintain the catheter if it is functional and there is an ongoing need for the catheter, in which case long-term anticoagulation should be continued as long as the catheter remains. In patients whose catheter is removed or if the UE DVT is not associated with a catheter, a 3-month duration of anticoagulation treatment is recommended.
Pulmonary embolism is classified as massive, submassive/intermediate risk, or nonmassive/low risk. Traditionally, massive PE was defined by the Miller index23 and later by the computed tomography (CT) obstruction index,24 which calculated the burden of emboli by angiography and CT, respectively. These indices had limited clinical use due to their inability to correlate emboli burden with mortality and morbidity.
Noting these shortcomings and the variable definitions of severity of PE, Jaff et al25 used mortality data from the International Cooperative Pulmonary Embolism Registry26 and the Management Strategy and Prognosis of Pulmonary Embolism Registry27 to propose definitions for massive, submassive/intermediate-risk, and low-risk PE. Massive PE was defined as acute PE with sustained hypotension (systolic blood pressure < 90 mm Hg), pulselessness, or profound bradycardia with symptoms of shock. Submassive or intermediate-risk PE was defined as acute PE without systemic hypotension (systolic blood pressure ≥ 90 mm Hg) but with either RV dysfunction or elevation of troponin I or T indicative of myocardial injury. Right ventricular dysfunction was further defined as RV systolic dysfunction on echocardiography, RV dilation (right ventricle diameter divided by left ventricle diameter > 0.9), elevated brain natriuretic peptide (BNP) > 90 pg/mL, and electrocardiogram (ECG) changes. Finally, low-risk or nonmassive PE was defined as acute PE without clinical markers that define massive or submassive PE.
Rapid diagnosis of RV dysfunction in patients with PE is important. Physical exam, laboratory values, and ECG findings are nonspecific and not consistently seen in patients with PE, and therefore cannot be used alone to diagnose or rule out PE. RV dysfunction may be identified on CT pulmonary angiography and is characterized by abnormal bowing or straightening of the interventricular septum toward the left ventricle (Figure 1). Additional findings on computed tomography angiography (CTA) of RV dysfunction include reflux of contrast into the inferior vena cava (IVC) due to increased right heart pressures (Figure 2), and RV to LV diameter ratios > 1.0.28 Right ventricular dysfunction is also identified on echocardiography, manifesting as RV to LV end diastolic diameter ratio > 1.0, abnormal bowing of the interventricular septum toward the left ventricle, RV end diastolic diameter > 30 mm, or loss of inspiratory collapse of the IVC. In addition, a finding named the McConnell sign was described in which hypokinesis of the right ventricle occurs and specifically involves the right ventricle free wall and base with sparing of the right ventricle apex and was found to have a sensitivity and specificity of 77% and 94%, respectively, in diagnosing PE.29,30
Right ventricular dysfunction can be diagnosed using criteria-based findings from CT or echocardiography.31 Irrespective of whether diagnosed on CT or echocardiography, RV dysfunction is associated with poor outcomes in patients with hypotension or massive PE.12,13,32–34 On the other hand, in normotensive patients, research has both supported35–47 and questioned12,38–40,48 the prognostic value of RV dysfunction. The presence of RV dysfunction and its correlation with mortality in submassive PE or intermediate-risk patients has not been established.
Diagnosis of PE
Clinical presentations of acute PE are often variable and nonspecific. Classically, patients present with chest pain, dyspnea, and hemoptysis, but, as with many other classic presentations, these symptoms as a whole occur in fewer than 20% of patients.49 Data from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study showed that 97% of patients exhibited ≥ 1 of the following symptoms: dyspnea, pleuritic chest pain, and tachypnea.50 The varied clinical presentation seems to depend on the burden of pulmonary emboli and a patient’s coexistent comorbidities and basal cardiopulmonary function. Therefore, clinical signs and symptoms alone cannot be used to confirm or exclude the presence of PE, but can be used to increase the clinician’s suspicion of PE and dictate laboratory or radiologic testing.
Even though the clinical presentation and patient characteristics are neither sensitive nor specific in the diagnosis of PE, the combination of these variables can be used to predict the probability of PE and have been standardized in the form of prediction rules, the most commonly used being the Wells score and revised Geneva rule, which are described below and in Tables 3 and 4.
Clinical Prediction Rules
The most commonly used method for assessing pretest probability is the Wells score (Table 3), which was first introduced in 199551 and later revised in 1998.52 The possibility of pulmonary embolism was based on clinical signs and symptoms as well as a patient’s risk factors for PE, the presence of DVT, and whether the clinician believed that an alternative diagnosis was less likely than the diagnosis of PE. This final criterion has been cited as a limitation, as it is subjective and not standardized, but it can heavily influence the Wells score. Wells showed prevalences of 3.4% in the low-probability category, 27.8% in the intermediate-probability category, and 78.4% in the high-probability category.52
Revised Geneva Score
The Geneva score (Table 4) was originally introduced in 2001 by Wicki et al.53 This scoring system was similar to the Wells score in predicting PE with prevalences of PE of 10% in the low-probability category, 38% in the intermediate-probability category, and 81% in the high-probability category. However, the first iteration of the Geneva score was limited in that it required an arterial blood gas measurement in room air, which may not be routinely obtained or may be skewed in patients receiving supplemental oxygen. Therefore, the Geneva score was revised in 2006 by Le Gal et al54 and uses only clinical variables. The revised Geneva score demonstrated similar stratification of PE probability as the original score with prevalences of 8%, 29%, and 74% in the low-, intermediate-, and high-probability categories, respectively.54 The revised Geneva score was further validated in a study by Klok et al55 in 2008, which compared the revised Geneva score to the Wells score and demonstrated statistically similar performance in prediction of PE.
An advantage of the Geneva score is that a clinician’s subjective assessment of alternative diagnoses is not included in the calculation of the score. Although a study by Iles et al56 showed that the experience of the clinician did not affect either the Geneva or Wells scores, the Geneva score was more consistent between junior and senior clinicians. Despite the availability of proven pretest probability scoring systems for PE, many clinicians prefer to use their clinical experience and judgment or gestalt over the scoring systems in the evaluation of patients with suspected PE,57 and recall of specific elements of these PE scoring systems among clinicians surveyed was not high. This implies that referencing and calculation of these probability scores may be cumbersome, which limits their use. A recent study by Kline and Stubblefield58 compared a clinical gestalt with pretest probability scoring and found that even though clinicians tended to overestimated their pretest probability with a clinical gestalt, diagnostic accuracy for PE was similar to that of scoring systems.
In addition to clinical prediction rules, laboratory testing has been analyzed in an attempt to provide more objective criteria in the diagnosis of PE. The most useful laboratory test in excluding PE is the D-dimer. Other tests have been analyzed and are of limited use for the inclusion or exclusion of PE but may be useful in identifying patients who have a poor prognosis.59–61
D-dimer is a fibrin degradation product and is named for its chemical composition as 2 cross-linked D fragments of the fibrin protein. D-dimer is not a specific test, as it can be elevated in a wide range of conditions such as old age, recent surgery, immobility, and pregnancy.62 Therefore, D-dimer is of limited use in hospitalized or chronically ill patients. On the other hand, a negative D-dimer test with a low or intermediate pretest probability by Wells or Geneva scores has been shown to be highly sensitive and excludes PE.63,64
Arterial Blood Gas
In the past, it was thought that a normal alveolar-arterial oxygen gradient excluded PE. However, numerous studies have shown that this gradient as well as various combinations of arterial blood gas measurements are of limited use in excluding PE.65,66
The diagnostic algorithm for chest pain often includes cardiac troponins I and T, which are released in the event of cardiac injury. Troponins are commonly part of the normal workup for chest pain and shortness of breath. In a meta-analysis by Becattini et al,67 conventional troponin I or T in patients with acute PE was associated with increased mortality and adverse outcome events in all patients as well as the subgroup of submassive/intermediate-risk PE.67 Other studies have a similar association of conventional troponin I or T, especially in combination with other diagnostic tests.32,59,60,68–71 Based on these results, troponins are most useful for risk stratifying patients when combined with other diagnostic tests, especially those demonstrating RV dysfunction. Additionally, a study by Kucher et al70 found that a combination of a negative troponin I and normal echocardiogram had the lowest risk of short-term mortality.
Brain Natriuretic Peptide
Brain natriuretic peptide (BNP), a protein released by the ventricles in response to excessive stretching of cardiac muscle, is not a specific test and is often used in the evaluation for heart failure. Similar to cardiac troponins, this test is not specific for PE but is useful in risk stratification of patients with PE. Tulevski et al61 found significant elevations in BNP in patients with RV dysfunction due to acute PE, and BNP has also been associated with increases in mortality and adverse outcomes.72–74 Kucher75 demonstrated, in a sample size of 73 consecutive patients treated with standard anticoagulation, that a lower cutoff value of BNP < 50 pg/mL was associated with a benign outcome in 95% of patients with PE.
Similar to the previously described clinical presentation of PE, ECG findings in acute PE vary depending on the burden of pulmonary emboli and the degree of occlusion. These include ECG abnormalities such as sinus tachycardia, atrial fibrillation, premature atrial or ventricular complexes, right axis deviation, right bundle branch block, and nonspecific ST abnormalities.76 Studies have shown that the ECG is normal in as few as 15% to 27% of patients76 or in as many as 53% of patients.77 The traditional S1Q3T3 ECG pattern, a large S wave in lead 1, a large Q wave in lead 3, and an inverted T wave in lead 3, was first described by McGinn and White78 in 1935 in cases of PE with high degrees of occlusion and RV strain (Figure 3). However, a recent study by Bajaj et al77 showed that this ECG pattern was found in only 6% of patients with PE, and, in a study by Rodger et al,79 this S1Q3T3 pattern is nonspecific and can be seen in patients with or without PE. This latter study also found that only tachycardia and incomplete right bundle branch block were statistically significant in the diagnosis of PE but were only marginally more frequent in patients with PE. As such, the ECG alone has limited diagnostic utility in suspected PE, and, as with the clinical presentation, should be used to increase suspicion of PE.79
Echocardiography is not a recommended test in the diagnosis of suspected PE as it is not useful in detecting or ruling out PE. However, it can be helpful in determining the risk of mortality or adverse outcomes, as RV dysfunction can be reliably diagnosed. As previously discussed, the prognostic role of RV dysfunction in PE is currently debated. Additionally, a patent foramen ovale, implicated as a risk of embolic cerebrovascular events when the patent foramen ovale diameter is > 4 mm, can be diagnosed with echocardiography.80 Free-floating thrombi within the right heart can be visualized as well, and are associated with PE and a high rate of mortality.81 Finally, the use of echocardiography has been advocated in evaluating RV response to thrombolytic therapy when obtained before and after treatment.82
Traditionally, the gold standard in diagnosis of pulmonary embolism has been catheter angiography, but this technique is infrequently used due to its invasive nature despite studies demonstrating its safety and low complication rate.83,84 Since its introduction, CTPA has been used in the diagnosis of PE, which manifests as filling defects within the pulmonary arteries (Figure 4). With early-generation helical CT scanners, overall sensitivity was 69% with a specificity of 84% and was deemed unreliable for excluding PE.85 This was likely due to artifacts, increased image acquisition time, and limited spatial resolution of images. Advancements in CT technology, namely multidetector row technology, faster image acquisition, software and techniques to eliminate or minimize artifact, and increased spatial resolution, have made CTPA more sensitive and accurate. Winer-Muram et al86 demonstrated 100% sensitivity and 91% accuracy when comparing CTPA to catheter pulmonary angiography. In addition, in cases where PE is ruled out by CTPA, other causes of chest pain or dyspnea may be diagnosed using CTPA of the chest.
The radiation dose is a disadvantage of using CTPA, and therefore judicious use of CT should be exercised with all patients, especially those who should avoid ionizing radiation, such as pregnant women. In the future, as CT technology and spatial resolution of CT continues to improve, methods to reduce radiation while maintaining diagnostic resolution will continue to emerge, and the risks associated with radiation versus the benefits of CT will need to be reassessed. Additionally, CTPA requires iodinated contrast, and therefore it is contraindicated in patients with contrast allergy or severely impaired renal function.
Magnetic Resonance Angiography
Similar to the advent of CTA, recent advancements in imaging protocols and magnetic resonance technology have led to shorter acquisition times and improved spatial resolution, raising the possibility of using magnetic resonance angiography (MRA) in the diagnosis of PE. A meta-analysis published in 2003 reported sensitivities of 77% to 100% and specificities of 95% to 98% for MRA.87 Diagnosis of central, lobar, and segmental PE is high with MRA, but detection of subsegmental PE has been estimated as low as 40%.88
An advantage of MRA over CTA is the avoidance of ionizing radiation and its associated risks. On the other hand, magnetic resonance imaging is not as widely available as CT nor is it as cost-effective. Currently, Medicare reimburses for MRA only in cases where iodinated contrast for CT is contraindicated.89 One final disadvantage of MRA is that its sensitivity for alternative diagnoses if PE is ruled out is less than that of CT.
Nuclear Medicine Ventilation/Perfusion (V/Q) Scans
First introduced in 1964 by Wagner et al,90 ventilation and perfusion scintigraphy with a concomitant chest X-ray has been used in the diagnosis of PE. During the ventilation portion of the exam, images are obtained viewing the distribution of inhaled gas containing radionuclides in the lungs. Technetium-99m–radiolabeled albumin is injected intravenously, and images are obtained to evaluate the segmental distribution of blood flow. Interpretation of V/Q scans is based on defects on the perfusion scan that are mismatched on the ventilation scan (Figure 5). Patients are categorized as normal, very low, low, intermediate, or high probability of PE. The low-, intermediate-, and high-probability categories have < 20%, 20% to 80%, and > 80% likelihood of PE, respectively. A perfusion defect without corresponding ventilation defect has a high probability of PE. A perfusion defect with a matched ventilation defect has a low probability of PE. Matched perfusion defects corresponding to abnormalities on chest X-ray, as in chronic obstructive pulmonary disease, have intermediate probability of PE.
A shortcoming of V/Q scanning occurs in the low- and intermediate-probability categories, both of which are considered indeterminate for PE. Mayo et al91 in 1997 demonstrated superior sensitivity of spiral CT over V/Q scanning (87% vs 65%) with similar specificities (95% vs 94%).91 This study also indicated that interobserver agreement was better with helical CT. More recently, in the PIOPED II study, 26.5% of patients had either a low- or intermediate-probability V/Q scan. Subanalysis of the patient cohort with proven PE showed that V/Q scanning had a sensitivity of 77.4% and a specificity of 97.7%.92
With the rapid advancements in CT technology, CTA has overtaken V/Q scanning as the imaging modality of choice for diagnosing PE.93 Advantages of CT over V/Q scans include the wide availability and rapidity of CT compared with nuclear medicine, the ability to diagnose alternate etiologies, increased spatial resolution, and the relative lack of nondiagnostic results.92 These advantages make CTA the go-to diagnostic imaging modality for diagnosis of PE. V/Q scanning does have a few advantages over CT, namely less radiation and lack of iodinated contrast, while maintaining adequate diagnostic yield, which secures its place in the diagnostic algorithm of PE in patients in whom CTA is contraindicated.
Venous Duplex Ultrasound
Duplex ultrasound searches for DVT by visualizing the veins and evaluating their compressibility (Figures 6 and 7). Evidence of concurrent proximal DVT or DVT in the thighs or higher would indicate a higher probability of PE in the clinical presentation.94,95 This is especially helpful in patients with nondiagnostic, low- or intermediate-probability V/Q scans, where PE cannot be ruled in or ruled out. Several studies have demonstrated that in approximately 80% of patients studied who had a nondiagnostic V/Q scan and a negative proximal venous duplex ultrasound, PE was ruled out.96,97 As such, a lower extremity venous duplex ultrasound is recommended in cases where PE is suspected but the V/Q scan results indicate a low or intermediate probability of PE.97,98
Treatment of PE
Nonmassive and Submassive PE
If the clinical probability of PE is high, treatment should begin prior to confirmatory testing. If there is low clinical suspicion for PE, treatment can be delayed until after confirmatory tests are performed. However, a pretest probability of 30% for PE in patients without contraindication to anticoagulation has been suggested as the threshold to begin empiric anticoagulation treatment if imaging or testing would delay treatment for > 24 hours.95
The mainstay of treatment for acute PE without hypotension, that is, nonmassive and submassive PE, is systemic anticoagulation. The most recent American College of Chest Physicians guidelines22 recommend a standard treatment regimen, which entails beginning a course of preferably low molecular weight heparin (LMWH) or fondaparinux, or less preferably, unfractionated heparin 5 days prior to starting the oral vitamin K antagonist warfarin, with ≥ 2 days of overlap between intravenous and oral medications with a goal of maintaining an international normalized ratio (INR) between 2 and 3 prior to discontinuing heparin.99 Heparin binds and activates antithrombin III, which in turn inactivates thrombin and the clotting cascade, whereas fondaparinux, a factor Xa inhibitor, inhibits the conversion of prothrombin to thrombin.
Thus far, there is no evidence that a specific method is superior to others in terms of preventing recurrence of VTE. Studies have shown that LMWH and fondaparinux have similar efficacy and safety as that of unfractionated heparin.100,101 However, the choice of initial anticoagulant may stem from other concurrent clinical situations. Dosing and ease of use of LMWH and fondaparinux are preferred to unfractionated heparin as they are dosed twice daily and once daily, respectively, whereas unfractionated heparin requires a bolus dose followed by continuous intravenous infusion and monitoring of partial thromboplastin time (PTT).102 Unfractionated heparin, as compared with LMWH, also has an increased risk of heparin-induced thrombocytopenia, which can be complicated by VTE.103,104 Unfractionated heparin is preferred in patients who have severely decreased renal function, as LMWH and fondaparinux are renally excreted,105 or when there is a need for rapid reversal of anticoagulation.
Newer oral anticoagulants have been developed in light of difficulties encountered with traditionally used anticoagulants. As such, newer therapies have been developed, tested, and compared with conventional therapy and have been shown to be as effective and safe. Rivaroxaban and apixaban are new factor Xa inhibitors, and dabigatran is a direct thrombin II inhibitor; they are approved by the US Food and Drug Administration (FDA) for the treatment of VTE. Studies have shown similar efficacy as well as safety profiles that are similar to or better than those of traditional therapies in terms of initial and long-term treatment of PE.106–111 These newer oral anticoagulants have advantages over traditional anticoagulants in that they do not require parenteral heparin bridging to oral therapy, are orally dosed once or twice daily, do not require regular laboratory monitoring, and do not have interactions with food. Their main disadvantage is that there is currently no specific antidote to reverse their effects.112,113 These newer oral anticoagulants are summarized in Table 5.
As previously described, the subset of submassive/intermediate-risk patients with PE, those with evidence of RV dysfunction without systemic hypotension, has not been as extensively studied, and treatment recommendations for this group are not yet known. Studies have evaluated the potential benefits of adding intravenous thrombolysis using alteplase, which is currently only FDA approved for use in massive PE, to conventional anticoagulant treatment regimen in patients with submassive PE. In a study by Konstantinides et al,38 mortality rates were not significantly different between groups of patients receiving traditional anticoagulation using heparin versus those receiving both heparin and alteplase. Konstantinides et al found that patients receiving both heparin and alteplase performed better clinically than those receiving heparin alone, and advocated the use of intravenous thrombolysis in patients with submassive PE. A similar study by Hamel et al39 did not support the use of thrombolytics in treating patients with submassive/intermediate-risk PE.
Recently, in the Pulmonary EmbolIsm THrOmbolysis (PEITHO)114 and Tenecteplase Or Placebo: Cardiopulmonary Outcomes At Three months (TOPCOAT) trials,115 patients with intermediate-risk PE treated with a single dose of tenecteplase demonstrated a significantly decreased short-term incidence of death or hemodynamic decompensation (in the PEITHO trial) and improved functional outcomes (in the TOPCOAT trial) compared with patients receiving standard anticoagulation. There was a significantly increased risk of intracranial and other bleeding complications in the PEITHO trial.114 At this time, the American College of Chest Physicians22 and Jaff et al25 recommend only systemic thrombolytic therapy for those patients at low risk for bleeding complications and who develop new hemodynamic instability.
In hemodynamically unstable patients, that is, those with prolonged systolic hypotension, more aggressive treatments, such as intravenous or catheter-directed thrombolysis, may be considered due to the increased risk of death. Systemic thrombolysis was shown to reduce the risk of death or recurrent PE by 55% in a meta-analysis.116 Major bleeding complications do occur with systemic thrombolysis in approximately 20% of cases, most commonly gastrointestinal or retroperitoneal.117 The only FDA-approved drug for systemic thrombolysis for patients with massive PE and acceptable risk of bleeding is alteplase,25 which is administered as a continuous infusion. Unfractionated heparin is the preferred anticoagulant to be used with alteplase, as it is short-acting and can be rapidly reversed.118 Therefore, unfractionated heparin should be used for initial anticoagulation in cases in which thrombolytic therapy is also considered119 and is withheld during the 2-hour infusion period for alteplase.120
Catheter-directed thrombolysis or mechanical thrombectomy is recommended only in patients with proximal PE who have absolute contraindications to systemic thrombolysis or surgical embolectomy, or those who have failed thrombolytic therapy.25,121 These interventions are also not recommended for patients with low-risk or submassive PE with minor RV dysfunction or myocardial necrosis and no clinical worsening.25 The goal of these techniques, again, is to remove or reduce clot burden, to ultimately reduce hemodynamic dysfunction due to PE. Catheter-directed thrombolysis theoretically enables administering significantly smaller doses of thrombolytics and is directed at the site of emboli, which theoretically should reduce the risk of bleeding complications.122,123 In a meta-analysis by Kuo et al,124 catheter-directed thrombolysis had a much lower rate of hemorrhagic complications, including intracranial hemorrhage, compared with systemic thrombolysis while demonstrating a clinical success rate of 86% in the stabilization of hemodynamics, resolution of hypoxia, and survival from massive PE, and therefore may be a relatively safe and effective treatment for acute massive PE. Catheter-directed thrombolysis may be used as an adjunct to mechanical thromboectomy, but clinical experience and outcomes with percutaneous thrombectomy devices are limited. None of the devices has been rigorously tested or FDA-approved for acute PE.
Another device that has been used in the treatment of acute massive PE is the EkoSonic ultrasound-assisted thrombolysis infusion device (EKOS Corporation, Bothell, WA). Chamsuddin et al122 performed a retrospective study evaluating patients treated with this device and found that it was effective at removing thrombus and had the potential to shorten the time of lysis and decrease the dose of thrombolytics. Another study by Stambo and Montague125 had similar findings with complete resolution of emboli without complication and a lower dose of thrombolytics. In a study comparing the EKOS device with catheter-directed thrombolysis, Lin et al126 demonstrated improved treatment outcomes with 100% removal of thrombus with the EKOS device while maintaining similar rates of mortality and significantly reduced complication rates.
More recently, investigators in the ULtrasound accelerated ThrombolysIs of pulMonAry embolism (ULTIMA) trial found that treatment of submassive/intermediate-risk patients with thrombolysis using the EKOS device resulted in significant reduction in RV dilation, and indirectly dysfunction, compared with standard anticoagulation without significantly increased bleeding complications.127 Additionally, the findings of the SEATTLE-II trial (a prospective, single-arm, multicenter trial of the EkoSonic endovascular system and Activase for treatment of acute pulmonary embolism) were recently presented at the 2014 American College of Cardiology Annual Conference and demonstrated similar significant reduction in RV dilation in patients with massive and submassive PE using ultrasound-assisted thrombolysis with the EKOS device without significantly increased bleeding complications, and only 1 death was attributed to PE at a 30-day follow-up.128 Finally, a recently-published case series by Jain et al,129 consisting of 5 patients with submassive/intermediate-risk PE, showed that ultrasound-assisted thrombolysis resulted in improvement in clinical symptoms and RV dysfunction without major bleeding complications.
Inferior Vena Cava Filters
Inferior vena cava filters function to prevent large emboli from the lower extremities from reaching the lungs and causing PE. Candidates for IVC filter placement are those patients who have DVT within proximal deep veins and have contraindications to anticoagulant therapy, recurrence or extension of VTE despite adequate anticoagulation, and inability to achieve or maintain therapeutic anticoagulation. The goal of IVC filter placement is to prevent pulmonary emboli or recurrence of emboli. Temporary IVC filters have been advocated in cases where patients have a time-dependent contraindication to anticoagulation or in patients undergoing procedures that carry an inherent risk of bleeding and a high risk of VTE.
The ease and low complication rates associated with IVC filter placement have increased their use; however, only a few randomized controlled trials have been performed to assess their efficacy. Long-term studies performed by the Prévention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) group evaluated the efficacy and safety of IVC filters compared with heparin therapy at 2-year130 and 8-year131 follow-up. The PREPIC group found that IVC filters significantly reduced the occurrence of PE, whereas the incidence of lower extremity DVT was increased in the filter group without significant differences in mortality between the filter and no-filter groups.131 Therefore, the PREPIC authors did not recommend widespread use of IVC filters for the prevention of PE. Recently, the DENALI trial, an interim analysis of a prospective, multicenter study of the Denali retrievable IVC filter, demonstrated effectiveness in the prevention of PE with low complication rates and high retrievability success of the filter even after long dwell times.132
Thus, as indicated with the above trials, there is no consensus on the generalized use of IVC filters in PE.133–135 Use of IVC filters is determined on a case-by-case basis and takes into account the risk of recurrent PE, the cardiopulmonary reserve, the severity of sentinel event, the response to anticoagulation, and other factors.
PE and Pregnancy
Pregnancy carries an increased risk of VTE, approximately 5 times higher in a pregnant woman compared with a similar age nonpregnant woman.136 The incidence has been estimated between 0.5 to 3.0 per 1000,137,138 and has been shown to occur more commonly in the postpartum period.139,140 This is likely due to the increased venous stasis and hypercoagulability that occur with physiologic changes of blood flow, volume, and coagulation factors during pregnancy and compression on the IVC and proximal iliac veins by the gravid uterus.
Diagnosis of PE in pregnant patients is complicated by the radiation dose received by the mother and the fetus during diagnostic imaging evaluation. The whole-body effective dose to the mother is generally higher with CT compared with V/Q. However, the intravenous radiopharmaceutical used in the perfusion phase of V/Q scanning is excreted primarily by the kidneys, and a significant radiation dose accumulates in the urinary bladder, and therefore is thought to place the fetus at risk. Although fetal radiation exposure has been estimated to be lower with V/Q scanning compared with CT,141–143 these radiation doses from both V/Q and CT rarely exceed 25 mGy, which is well below the established risk threshold of 50 to 100 mGy, and can be considered negligible.144 As such, the focus shifts toward reducing exposure to the mother, particularly to the breasts and lungs. Studies have shown that average radiation dose to the female breast during CT examination is 14 to 20 mGy.145,146
Therefore, in its most recent published guidelines for evaluation of suspected PE in pregnancy, the American Thoracic Society recommends an initial evaluation with a chest X-ray in pregnant patients with suspected PE.147 If this chest X-ray is normal, V/Q scan is recommended, and if the chest X-ray is abnormal, a CT is recommended.147 In patients with suspected PE and symptoms of DVT, an initial evaluation with bilateral lower extremity venous compression ultrasound is recommended.147 In postpartum patients, the risks and benefits of greater whole-body and breast tissue radiation with CT must be weighed along with the fact that a breast-feeding mother must refrain from breast-feeding for approximately 24 hours after V/Q scanning.148
Treatment of PE in pregnant women is similar to that in nonpregnant patients, with the mainstay of treatment being anticoagulation with either LMWH or unfractionated heparin. However, due to concerns of osteoporosis and osteoporotic fracture associated with unfractionated heparin after a study performed by Pettilä et al,149 the American College of Chest Physicians recommends LMWH over unfractionated heparin for the treatment of VTE in pregnant patients.150 Warfarin should be avoided during pregnancy due to its well-documented teratogenic effects. The American College of Chest Physicians guidelines recommend continuation of anticoagulants for ≥ 6 weeks postpartum for a minimum total duration of therapy of 3 months.
Inferior vena cava filters have been deemed safe and effective in pregnant women with proximal lower extremity DVT for prevention of PE.151-153 Suprarenal positioning of the IVC filter is generally recommended. Indications for IVC filter placement are similar to those for nonpregnant patients and are advocated in patients with contraindications to anticoagulation, occurrence of PE despite adequate prophylaxis, and the extension of proximal lower extremity DVT despite therapeutic anticoagulation.154,155
Finally, concerning the use of systemic thrombolytic therapy for treatment of PE in pregnancy, the literature remains limited to case reports. Prior literature reviews performed by Turrentine et al156 in 1995, Leonhardt et al157 in 2006, and Te Raa et al158 in 2009 have reported overall favorable results with systemic thrombolysis for acute massive PE. Turrentine et al reported 2 maternal deaths (1%), 14 maternal hemorrhagic complications (8.1%), and 10 fetal deaths (5.8%), with the majority of complications occurring with streptokinase. Leonhardt et al’s review included 7 cases of PE treated with recombinant tissue plasminogen activator (rt-PA) and reported no maternal deaths or hemorrhagic complications and 2 fetal deaths. Te Raa et al’s review of 13 cases since Leonhardt et al’s review reported no maternal deaths, 4 nonfatal maternal bleeding complications (30.8%), 2 fetal deaths (15.4%), and 5 preterm deliveries (38.5%).
Similarly, we conducted a literature review using PubMed with the search terms thrombolysis, pregnancy, and pulmonary embolism and found 11 additional case reports since Te Raa et al’s review, 3 using streptokinase, 6 using rt-PA, 1 using tenecteplase, and 1 using Monteplase.159–167 In all of these cases, no maternal deaths or major hemorrhagic complications and 2 fetal deaths were reported. Additionally, a recent case report by Dhutia et al168 describes a normotensive pregnant patient with acute submassive PE demonstrating severe RV dysfunction on echocardiogram successfully treated with a half dose of rt-PA without maternal or fetal complications.
Although research on systemic thrombolysis in pregnancy remains limited, the outcomes from numerous published case reports suggest that it is an effective and safe option in the treatment life-threatening maternal PE.
Acute PE can be associated with high rates of mortality. It is important to quickly categorize patients into massive, submassive, and nonmassive/low-risk PE based on a combination of clinical presentation, laboratory values, and imaging studies, as these categories have implications for mortality risk and treatment pathways. Chest CTA has become the diagnostic imaging modality of choice, although nuclear medicine V/Q scanning is the primary imaging modality for patients with contraindications to CT. Systemic anticoagulation with heparin and warfarin is still the mainstay of treatment for submassive PE, although newer anticoagulants are also effective and safe and are easier to dose and monitor. In massive PE, limited studies have shown that catheter-directed thrombolysis can be as effective as and safer than systemic thrombolysis. Devices for catheter-directed thromboembolectomy continue to emerge, and further studies must be performed to evaluate the efficacy and safety of these devices.
Conflict of Interest Statement
David Ho, DO, has no conflict of interest to declare. H. Bob Smouse, MD, is a consultant, adviser, and speaker at Boston Scientific Corporation and Cook Medical Inc.
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