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Treatment, prognosis, and follow-up of acute pulmonary embolism in adults

Treatment, prognosis, and follow-up of acute pulmonary embolism in adults
Author:
Aaron S Weinberg, MD, MPhil
Section Editors:
Jess Mandel, MD, MACP, ATSF, FRCP
Korilyn S Zachrison, MD, MSc
Deputy Editor:
Geraldine Finlay, MD
Literature review current through: Nov 2022. | This topic last updated: Jul 08, 2022.

INTRODUCTION — Acute pulmonary embolism (PE) is a common and sometimes fatal disease with a variable clinical presentation. It is critical that therapy be administered in a timely fashion so that recurrent thromboembolism and death can be prevented [1-5].

The treatment, prognosis, and follow-up of patients with acute PE are reviewed here. The epidemiology, pathophysiology, clinical presentation, and diagnosis of PE, as well as detailed discussions of anticoagulation and thrombolysis in patients with PE are presented separately. (See "Overview of acute pulmonary embolism in adults" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration" and "Venous thromboembolism: Initiation of anticoagulation".) (Related Pathway(s): Pulmonary embolism (confirmed or suspected): Initial management of hemodynamically stable adults and Pulmonary embolism (confirmed or suspected): Initial management of hemodynamically unstable adults.)

The approach to treatment outlined in this topic is, in general, consistent with strategies outlined by several international societies including the American College of Chest Physicians, the American College of Physicians, the European Society of Cardiology, the European Respiratory Society, the American Society of hematology, and others [6-10].

INITIAL APPROACH AND RESUSCITATION — The initial approach to patients with suspected pulmonary embolism (PE) should focus upon stabilizing the patient while clinical evaluation and definitive diagnostic testing are ongoing. Anticoagulation should be initiated even prior to confirming the diagnosis of PE if risk benefit regarding suspicion of PE and risk of bleeding appear favorable. Once diagnosis is confirmed, risk stratification is crucial.

Assess hemodynamic stability — The initial approach to patients with suspected PE depends upon whether the patient is hemodynamically stable or unstable as shown in the algorithm (algorithm 1A-B). (See "Overview of acute pulmonary embolism in adults", section on 'Nomenclature'.)

Hemodynamically unstable PE, ie, high-risk or "massive" PE is that which presents with hypotension; hypotension is defined as a systolic blood pressure (BP) <90 mmHg for a period >15 minutes or a drop in systolic blood pressure substantially below baseline (generally a drop of >40 mmHg, hypotension requiring vasopressors, or clear evidence of shock). Importantly, these high-risk patients are a heterogeneous group [8] with the extremely unstable patients suffering cardiac arrest.

Hemodynamically stable PE is defined as PE that does not meet the definition of hemodynamically unstable PE. These patients are also a very heterogeneous group ranging from patients with small PE, stable BP, normal right ventricular size and function and normal biomarkers, with a normal simplified pulmonary embolism severity index (sPESI) ("low risk") to those patients with extensive emboli with tachycardia, right ventricular dysfunction, abnormal biomarkers, and borderline BP (ie, intermediate risk "submassive" PE). Based upon the European Society of Cardiology (ESC) guidelines [8], these patients have been categorized as "intermediate-low risk" (abnormal right ventricular function or elevated serum troponin) and intermediate-high risk (abnormal right ventricular function and elevated serum troponin).

Importantly, patients may become hemodynamically stable following resuscitation, or become unstable during the evaluation and early treatment period, both of which necessitate rapid redirection of therapeutic strategies.

Hemodynamically stable — The majority of patients with PE are hemodynamically stable upon presentation [11]. The initial approach should focus upon general supportive measures while the diagnostic evaluation is ongoing; supportive measures include the following (see "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and 'Hemodynamically stable patients' below):

Peripheral intravenous access with or without intravenous fluids (see 'Hemodynamic support' below)

Oxygen supplementation (see 'Respiratory support' below)

Empiric anticoagulation depending upon the clinical suspicion for PE, risk of bleeding, and expected timing of definitive diagnostic tests (see 'Empiric anticoagulation' below)

Hemodynamically unstable — A small percentage of patients with PE present with hemodynamic instability or shock (approximately 8 percent, ie, high-risk or "massive" PE). When patients with suspected PE present with hypotension, initial support should focus upon restoring perfusion with intravenous fluid resuscitation and vasopressor support, as well as oxygenation and, if necessary, stabilizing the airway with intubation and mechanical ventilation. (See 'Hemodynamic support' below and 'Respiratory support' below and "Overview of acute pulmonary embolism in adults", section on 'Nomenclature'.)

For most patients who become hemodynamically stable following resuscitation and in whom the clinical suspicion for PE is high, we prefer immediate anticoagulation with unfractionated heparin and prompt imaging for definitive diagnosis (usually computed tomographic pulmonary angiography [CTPA]). For patients with a moderate or low suspicion for PE, the use of empiric anticoagulation depends upon the timing of diagnostic testing. Diagnostic testing in patients with suspected PE is presented elsewhere. (See 'Empiric anticoagulation' below and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Hemodynamically stable patients'.)

For patients with a high clinical suspicion for PE who are hemodynamically unstable (ie, systolic blood pressure <90 mmHg for >15 minutes, hypotension requiring vasopressors, or clear evidence of shock), and in whom transfer to radiology for a CTPA is considered unsafe, a portable perfusion scan can be done at some centers. When portable perfusion scanning or CTPA is not available or is unsafe, we prefer bedside echocardiography (transthoracic or transesophageal) to obtain a presumptive diagnosis of PE (right ventricle enlargement/hypokinesis, regional wall motion abnormalities that spare the right ventricular apex [McConnell's sign], or visualization of clot) prior to the empiric administration of systemic thrombolytic therapy (ie, reperfusion therapy). If bedside echocardiography is delayed or unavailable, the use of thrombolytic therapy as a life-saving measure should be individualized; if not used, the patient should receive empiric anticoagulation. The initiation of anticoagulation should not be delayed while considering other, more aggressive interventional therapies. We suggest a similar approach for select patients with known PE whose course becomes complicated by hypotension during anticoagulation in whom the suspicion for recurrent PE despite anticoagulation is high. (See 'Hemodynamically unstable patients' below.)

For patients with suspected PE who remain hemodynamically unstable and the clinical suspicion is low or moderate, the approach to empiric anticoagulation should be the same as for patients who are hemodynamically stable; empiric thrombolysis is not justified in this population.

The echocardiographic findings suggestive of PE and the diagnostic approach to hemodynamically unstable patients, as well as the indications for thrombolytic therapy and its alternative, embolectomy, are discussed separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Echocardiography' and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Hemodynamically unstable patients' and 'Embolectomy' below and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Hemodynamically unstable patients (high-risk pulmonary embolism)'.)

Pulmonary embolism response teams — The decision to administer thrombolysis is strongly influenced by additional clinical factors. For example, while a patient with proven PE-induced shock who is unconscious requiring very high doses of pressors is a candidate for immediate intravenous thrombolytic therapy, a patient who has low blood pressure for 20 minutes but who is awake, alert, and comfortable, with low oxygenation requirement might be considered for anticoagulation alone, or a catheter-based interventional procedure. Thus, when feasible, it is prudent to adopt a multidisciplinary approach to facilitate management of hemodynamically unstable patients with PE as well as selected patients with intermediate-high risk PE; some centers have incorporated a "pulmonary embolism response team" (PERT) to facilitate the process [12-14]. There are limited data that describe the impact of PERT. One single center retrospective study examined outcomes in patients with PE before and after the implementation of PERT [15]. PERT was associated with a reduction in 30 day inpatient mortality (4.7 versus 8.5 percent), lower rates of major bleeding (8.3 versus 17 percent), shorter time to therapeutic anticoagulation (12.6 versus 16.3 hours), and decreased use of inferior vena cava filters (22.2 versus 16.4 percent). The mortality benefit was most pronounced in the subgroup of patients with intermediate- and high-risk PE (5.3 versus 10 percent), suggesting that this population derive the greatest benefit from PERT. There was also an increased use of thrombolytic and catheter-based strategies that did not reach statistical significance. In contrast, in another single-center study of 2042 patients, among which 165 were evaluated by PERT, there was no difference in the mortality between the pre-PERT and post-PERT implementation phases [16]. The 2019 European Society of Cardiology (ESC) guidelines have included a discussion of the utility of PERT and given it a class IIa level C recommendation [8].

Initial therapies

Respiratory support — Supplemental oxygen should be administered to target an oxygen saturation ≥90 percent. Severe hypoxemia, hemodynamic collapse, or respiratory failure should prompt consideration of intubation and mechanical ventilation. Importantly, patients with coexistent right ventricle failure are prone to hypotension following intubation. Thus, in this population, it may be prudent to consult an expert in cardiovascular anesthesia and high plateau pressures should be avoided. The principles of intubation, mechanical ventilation, and extracorporeal membrane oxygenation (which has been used successfully in severely ill patients with refractory hypoxemia and/or hypotension), are discussed separately. (See "Induction agents for rapid sequence intubation in adults outside the operating room" and "Direct laryngoscopy and endotracheal intubation in adults" and "Extracorporeal membrane oxygenation (ECMO) in adults" and "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit", section on 'Indications'.)

Hemodynamic support — The precise threshold that warrants hemodynamic support depends upon the patient's baseline blood pressure and whether there is clinical evidence of hypoperfusion (eg, change in mental status, diminished urine output). In general, we prefer small volumes of intravenous fluid (IVF), usually 500 to 1000 mL of normal saline, followed by vasopressor therapy should perfusion fail to respond to IVF.

Intravenous fluid – IVF is first-line therapy for patients with hypotension. However, in patients with right ventricular (RV) dysfunction, limited data suggest that aggressive fluid resuscitation is not beneficial, and may be harmful [17-21]. The rationale for limiting IVF administration comes from preclinical studies and one small observational study in humans, which reported that small volumes of IVF increase the cardiac index in patients with PE, while excessive amounts of IVF result in RV overstretch (ie, RV overload), RV ischemia, and worsening RV failure. The patient's volume status should be carefully assessed as this could influence the approach to fluid administration.

Vasopressors – Intravenous vasopressors are administered when adequate perfusion is not restored with IVF. The optimal vasopressor for patients with shock due to acute PE is unknown, but norepinephrine is generally preferred (table 1) [18,22-24]. Options include:

NorepinephrineNorepinephrine is the most frequently utilized agent in this population because it is effective and less likely to cause tachycardia [18]. Other alternatives include dopamine and epinephrine, but tachycardia, which can exacerbate hypotension, can occur with these agents [22].

DobutamineDobutamine is sometimes used to increase myocardial contractility in patients with circulatory shock from PE. However, it also results in systemic vasodilation which worsens hypotension, particularly at low doses [23,24]. To mitigate this effect, we typically initially add norepinephrine to dobutamine; as the dose of dobutamine is increased, the effects of dobutamine-induced myocardial contractility exceed those of vasodilation, potentially allowing norepinephrine to be weaned off.

Isoproterenol, amrinone, and milrinone have been investigated in animal models, but have not proven useful for hypotension due to acute PE [25,26]. Physiologic properties and use of vasopressors are discussed separately. (See "Use of vasopressors and inotropes".)

Empiric anticoagulation — The administration of empiric anticoagulation depends upon the risk of bleeding, clinical suspicion for PE (calculator 1) (table 2) and the expected timing of diagnostic tests [5,21]. There is no optimal prediction tool for assessing bleeding risk in patients with PE. Similarly, while many experts propose use of the Wells score to assess the risk of PE, careful clinical judgment is acceptable and many experts use gestalt estimates, the details of which are discussed separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Determining the pretest probability of pulmonary embolism' and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'Assessing the risk of bleeding'.)

One strategy is shown below:

Low risk for bleeding – Patients without risk factors for bleeding (table 3) have a three-month bleeding risk of <2 percent; in such patients, empiric anticoagulation may be considered in the following patient groups:

A high clinical suspicion for PE (eg, Wells score >6)

A moderate clinical suspicion for PE (eg, Wells score 2 to 6), in whom the diagnostic evaluation is expected to take longer than four hours

A low clinical suspicion for PE (eg, Wells score <2), if the diagnostic evaluation is expected to take longer than 24 hours

Unacceptably high risk for bleeding – For patients with absolute contraindications to anticoagulant therapy (eg, recent surgery, hemorrhagic stroke, active bleeding) or those assessed by their clinician to be at an unacceptably high risk of bleeding (eg, aortic dissection, intracranial or spinal cord tumors), empiric anticoagulation should not be administered. The diagnostic evaluation should be expedited so that alternate therapies (eg, inferior vena cava filter, embolectomy) can be initiated if PE is confirmed.

Moderate risk for bleeding – Patients with one or more risk factors for bleeding (table 3) have a moderate (>3 percent) to high (>13 percent) risk of bleeding. In such patients, empiric anticoagulant therapy may be administered on a case-by-case basis according to the assessed risk-benefit ratio and the values and preferences of the patient. Additionally, use of these bleeding estimates should not preclude clinical judgment when making a decision to anticoagulate in this population. As an example, we might empirically anticoagulate a patient with moderate risk of bleeding if they have a high clinical suspicion for PE, severe respiratory compromise, or an expected delay for the insertion of a vena caval filter.

Typically, menstruation, epistaxis, and the presence of minor hemoptysis are not contraindications to anticoagulation but should be monitored during anticoagulant therapy. (See 'Monitoring and follow-up' below.)

The optimal agent for empiric anticoagulation depends upon the presence or absence of hemodynamic instability, the anticipated need for procedures or thrombolysis, and the presence of risk factors and comorbidities (table 4). As an example, low molecular weight heparin (LMW heparin) may be chosen for patients with hemodynamically stable PE who do not have renal insufficiency in whom rapid onset of anticoagulation needs to be guaranteed (ie, therapeutic levels are achieved with four hours). While unfractionated heparin may be preferred by most experts in patients who are hemodynamically unstable in anticipation of a potential need for thrombolysis or embolectomy, LMW heparin is not contraindicated in this setting. Direct thrombin and factor Xa inhibitors should not be used in hemodynamically unstable patients. (See "Venous thromboembolism: Initiation of anticoagulation".)

DEFINITIVE THERAPY

Our approach — For patients in whom the diagnostic evaluation excludes pulmonary embolism (PE) (see "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism"), anticoagulant therapy should be discontinued if it was initiated empirically, and alternative causes of the patient's symptoms and signs should be sought (algorithm 1A-B).

For patients in whom the diagnostic evaluation confirms PE, we suggest an approach that is stratified according to whether the patient is hemodynamically stable or unstable (algorithm 1A-B). At any time, the strategy may need to be redirected as complications of PE or therapy arise. (See 'Hemodynamically stable patients' below and 'Hemodynamically unstable patients' below.) (Related Pathway(s): Pulmonary embolism (confirmed or suspected): Initial management of hemodynamically stable adults and Pulmonary embolism (confirmed or suspected): Initial management of hemodynamically unstable adults.)

Hemodynamically stable patients — Patients in this group are heterogeneous and have a wide range of presentations as well as variable risk of recurrence and decompensation; it includes those with low-risk, intermediate-low risk, and intermediate-high risk PE.

We suggest the following approach for most hemodynamically stable (ie, normotensive) patients with low-risk and intermediate-low risk PE (algorithm 1A-B):

For those in whom the risk of bleeding is low, anticoagulant therapy is indicated. (See 'Anticoagulation' below.)

For those who have contraindications to anticoagulation or have an unacceptably high bleeding risk, placement of an inferior vena cava (IVC) filter should be performed. (See 'Inferior vena cava filters' below and "Placement of vena cava filters and their complications".)

For those in whom the risk of bleeding is moderate or high, therapy should be individualized according to the assessed risk-benefit ratio and values and preferences of the patient. As an example, a patient >75 years who is at risk of falling is not an ideal candidate for anticoagulation; anticoagulation may be considered if a vena cava filter cannot be placed (eg, inability to access the IVC due to extensive thrombus or tumor). (See 'Empiric anticoagulation' above.)

It should be noted that when PE is proven and anticoagulation is contraindicated, an IVC filter is still indicated, whether the PE is small or extensive and even in the absence of residual deep venous thrombosis (DVT).

For most hemodynamically stable patients, we recommend against thrombolytic therapy (eg, low risk patients).

Hemodynamically stable (ie, normotensive) patients with intermediate-risk/submassive PE who are anticoagulated, should be monitored closely for deterioration. Thrombolysis and/or catheter-based therapies may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of hemorrhage. Examples of such patients include those who have a large clot burden, severe RV enlargement/dysfunction, high oxygen requirement, and/or are severely tachycardic (table 5). The details of such therapies are discussed separately. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Systemic infusion (full-dose thrombolytic)'.)

Anticoagulation — Anticoagulant therapy is indicated for patients with PE in whom the risk of bleeding is low:

Initial anticoagulation – Initial anticoagulant therapy is administered as soon as possible to quickly achieve therapeutic anticoagulation. A detailed discussion of agent selection and patient selection for outpatient anticoagulation is presented separately. (See "Venous thromboembolism: Initiation of anticoagulation" and 'Outpatient anticoagulation' below.)

Long-term anticoagulation (after discharge) – All patients are anticoagulated for a minimum of three months. Agent selection and duration of long-term anticoagulation in patients with PE and DVT are discussed in detail separately. (See "Venous thromboembolism: Anticoagulation after initial management".)

Indefinite anticoagulation – Select patients with PE are candidates for indefinite anticoagulation. Patient selection depends upon the nature of the event (ie, provoked or unprovoked), the presence of risk factors (eg, transient or persistent), the estimated risk of bleeding and recurrence, as well as patient preferences and values (eg, occupation, life expectancy, burden of therapy), and trials that support a benefit. The rationale and indications for indefinite anticoagulation are described separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Outpatient anticoagulation — In select patients with PE, outpatient therapy can be administered by giving the first dose of anticoagulant in the hospital or urgent care center, with the remaining doses given at home. The decision to treat as an outpatient should be made in the context of the patient's clinical condition, understanding of the risk-benefit ratio, and their preferences. Although the ideal candidate is poorly defined, guideline groups, several randomized trials, and meta-analyses suggest that, in patients with PE, outpatient anticoagulation is safe and effective in carefully selected patients with all of the following features [5,27-38]:

Low risk of death – defined as pulmonary embolism severity index (PESI) class I or II (table 6), or simplified PESI (sPESI) score = 0 (see 'Prognostic models' below)

No requirement for supplemental oxygen

No requirement for narcotics for pain control

No respiratory distress

Normal pulse and blood pressure

No recent history of bleeding or risk factors for bleeding (table 3)

No serious comorbid conditions (eg, ischemic heart disease, chronic lung disease, liver or renal failure, thrombocytopenia, or cancer)

Normal mental status with good understanding of risk and benefits, are not needle averse (if low molecular weight [LMW] heparin chosen), and have good home support (eg, do not live alone, have access to a telephone and clinician, can return to the hospital quickly if there is clinical deterioration)

Absence of concomitant deep venous thrombosis (a high clot burden in the lower extremities may increase the risk of recurrence, death, or warrant additional therapy)

Support for outpatient therapy or early discharge following a brief inpatient stay is derived from randomized studies and meta-analyses with flawed methodology [9,31,33,35]. As examples:

One open label, multicenter trial randomly assigned 344 patients with symptomatic PE and a low risk of death (PESI I/II; (table 6)) to receive either inpatient (intravenous heparin followed by warfarin) or outpatient (subcutaneous low molecular weight heparin followed by warfarin) therapy [31]. Compared with inpatients, patients treated as an outpatient had a slightly higher rate of recurrent venous thromboembolism (VTE; 0.6 percent versus 0 percent) and major bleeding events (1.8 percent versus 0 percent) at 90 days that was not statistically significant. Mortality was no different between the groups (0.6 percent). The mean length of stay was 0.5 days for outpatients and 3.9 days for inpatients.

A 2013 meta-analysis of 21 studies compared patients at low risk of death who were anticoagulated for PE as an outpatient (discharged within 24 hours) with patients who were treated as an inpatient and discharged after 72 hours (randomized and observational studies were included) [33]. Compared with inpatient anticoagulation, outpatient anticoagulation was not associated with a statistically significant difference in the rate of recurrent VTE (1.7 versus 1.2 percent) and mortality (1.9 versus 0.74 percent), or major bleeding events (0.97 versus 1 percent); However, although absolute rates of recurrent VTE and death were higher with outpatient treatment, there was significant population and therapeutic regimen heterogeneity among the included studies, limiting the interpretation of the results. A 2018 analysis of two randomized trials reported low quality evidence that there was no difference in 30- or 90-day mortality, major bleeding, or recurrence between low risk patients with acute PE who were treated as an inpatient or outpatient [39]. In a 2021 meta-analysis of 14 studies of patients with low-risk PE, there was no difference in the mortality or recurrence rate or rate of major bleeding among patients treated as an outpatient or inpatient [35].

A retrospective analysis of 1127 patients reported that the 14 day rate of adverse events (recurrent VTE, major bleeding, or death) was 3 percent for outpatients compared with 13 percent for inpatients and the three-month rate was 7 and 22 percent, respectively [40].

In another randomized trial of 114 patients with PE who were discharged on rivaroxaban and were at low risk of death the LOS was significantly reduced in early discharge patients compared with those who were admitted (34 versus 5 hours) [41]. At three months, there were no bleeding events, recurrent VTE, or deaths.

In a prospective analysis of 525 patients with PE who were discharged early and treated with rivaroxaban, only three patients (0.6 percent) developed symptomatic non-fatal VTE recurrence at three months follow-up and bleeding rates were low (1.2 percent) [42].

The ideal agent is unknown. Agent selection for outpatient anticoagulant therapy in patients with PE is similar to that for deep vein thrombosis. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Outpatient versus inpatient therapy'.)

Despite the fact that outpatient anticoagulation has been shown to be safe, this practice may be uncommon. One retrospective review of 746 patients with PE who were potentially eligible for anticoagulation at home, reported that only 1.7 percent were treated at home and only 16 percent were discharged within two days [43]. However, clinician education may change this practice. As an example, in one trial of 1763 patients diagnosed with PE in the ED, an electronic intervention built into the electronic health record increased the number of patients who could be discharged to home (17 percent versus 28 percent) without increasing the risk of return visits to the ED, recurrent VTE, or mortality [44].

Patients with subsegmental PE — The increasing use of computed tomography (CT) has led to the increased diagnosis of incidental (asymptomatic) PE and small subsegmental PE (SSPE) (figure 1).

One observational study reported that 15 percent of patients with symptomatic PE have SSPE [45]. The true proportion of patients with asymptomatic SSPE is unknown [46].

Although the clinical relevance of SSPE is unknown, a single subsegmental defect probably does not have the same clinical outcome as a single segmental or lobar PE or multiple SSPE. A retrospective review of 222 patients with PE, 36 percent of whom had SSPE, reported that 87 percent were systemically anticoagulated while the remaining were not anticoagulated due to bleeding or poor prognosis at the time of diagnosis [47]. Adverse events were similar between SSPE patients and patients with more proximal emboli. (See "Overview of acute pulmonary embolism in adults", section on 'Nomenclature'.)

In patients with SSPE, the incidence of VTE recurrence is unclear but may be higher than that in the general population. While older retrospective studies suggested minimal recurrence, studies were flawed [48-50]. However, in the largest prospective study to date of 292 patients with isolated SSPE and no lower-extremity DVT who were managed without anticoagulation, the recurrence rate was 3.1 percent at 90 days, (ie, higher than the expected rate in the general population of approximately 1 percent or less) [51]. Rates were higher in those with multiple SSPEs compared with a single isolated PE (5.7 versus 2.1 percent) and higher in older patients compared with those younger than 65 years (5.5 versus 1.8 percent). No fatalities were reported. However, this study was stopped early for benefit, which may have influenced the results.

Whether or not patients with SSPE should be anticoagulated is controversial [9,52]. Practice varies widely; some experts anticoagulate all patients with SSPE, regardless of whether or not symptoms are present, while other experts avoid anticoagulation in a minority of individuals (especially if a more convincing etiology is discovered on CT for the patients' symptoms) [45].

Our approach to anticoagulating patients with SSPE is the following:

We believe that most patients with SSPE should be anticoagulated similarly to those who present with symptomatic or large lobar defects [5,9]. This is particularly important when VTE is unprovoked and persistent risk factors for VTE such as active cancer and acute hospitalization with prolonged immobility, are present; defects are multiple; symptoms are present; and/or when patients have limited cardiorespiratory reserve. (See "Venous thromboembolism: Anticoagulation after initial management" and "Venous thromboembolism: Initiation of anticoagulation".)

The optimal duration of anticoagulation is unknown but similar to patients with segmental or lobar PE, patients with SSPE should be treated for a minimum of three months. Anticoagulant therapy beyond that period should be individualized, the details of which are discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'Incidental subsegmental PE without identifiable risk factors'.)

Experts also agree that a small subset of patients with a single small defect (ie, seen on one image) in whom there is no evidence of proximal lower extremity DVT or evidence of thrombus elsewhere (eg, upper extremity clot) may reasonably opt for no anticoagulation, provided the risk of recurrence is considered low and patients are monitored appropriately [9].

Additional findings that may support this decision include those in whom a false positive test is suspected, the absence of persistent risk factors, those with preserved baseline cardiorespiratory function, and/or those in whom a low pretest probability and normal D-dimer is present.

When clinical surveillance is chosen, we suggest serial testing with bilateral proximal compression ultrasonography (CUS) of the lower extremities in two weeks to look for evidence of proximal thrombus. We also have a low threshold to repeat diagnostic imaging for PE should symptoms persist or recur. This strategy is based upon the rationale that serial CUS has been reported to be safe in patients with nondiagnostic testing for PE (eg, indeterminate or low probability ventilation perfusion scanning); details regarding this strategy are described separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Lower-extremity ultrasound with Doppler'.)

Inferior vena cava filter — In most patients, an inferior vena cava (IVC) filter is not necessary. For most patients with PE in whom anticoagulation is contraindicated, or patients in whom the risk of bleeding is unacceptably high, IVC filter should be placed. Similarly, an IVC filter is appropriate in patients who develop contraindications while on anticoagulation; however, placement in this population depends upon the planned duration of anticoagulation and risk of recurrence when anticoagulation is discontinued. Another more unusual indication for an IVC filter is recurrence despite therapeutic anticoagulation; a decision may be more difficult in patients who recur quickly after the onset of anticoagulation. Retrievable filters should be used such that once the contraindication has resolved, the filter can be removed and patients should be anticoagulated. The efficacy of IVC filters, their placement and complications, are presented separately. (See "Placement of vena cava filters and their complications" and 'Inferior vena cava filters' below and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Inferior vena cava filter'.)

When contraindications to anticoagulation are present in acute PE, an IVC filter should be placed even in the absence of proven lower extremity thrombus. Thrombus may remain undetected in the pelvis or calf veins or clot can quickly reform in the leg veins after embolization.

However, the decision to place an IVC filter, most of which are infrarenal, is modified in the following settings:

If the patient has confirmed extensive upper extremity thrombosis in the absence of lower extremity thrombosis, an IVC filter will not be effective; and a superior vena caval filter may be useful.

If the thrombus is in the renal vein (identified by the initial CT angiogram or during placement of the IVC filter), a suprarenal filter is appropriate.

Data describing outcomes in patients with PE who have IVC filters placed are limited:

A similarly designed randomized trial (PREPIC2) reported outcomes in 399 patients with severe PE (eg, older patients >75 years, active cancer, signs of right ventricle dysfunction, chronic respiratory insufficiency) who received either standard anticoagulation alone or anticoagulation plus an IVC filter that was retrieved at three months [53]. At three months, the addition of an IVC filter to anticoagulation did not alter the rate of PE recurrence (1.5 versus 3 percent), DVT recurrence (0.5 percent), or mortality (7.5 versus 6 percent). The lack of benefit associated with IVC filter placement was persistent at six months. The rate of filter complications (eg, thrombosis) was low (<2 percent).

Data derived from the Nationwide Inpatient Sample reported that the insertion of an IVC filter in hemodynamically stable patients with PE did not improve in-hospital mortality but was associated with a lower in-hospital case fatality rate among unstable patients who received thrombolytic therapy (8 versus 18 percent) as well as unstable patients who did not receive thrombolytic therapy (33 versus 51 percent) [54,55]. Another database analysis of over 13,000 patients with PE who were treated with either thrombolytic or anticoagulant therapy reported a reduction in in-hospital mortality in those who were adjunctively treated with an IVC filter compared with those who did not receive a filter (3 versus 5 percent) [56]. However, both of these studies are intrinsically flawed.

Hemodynamically unstable patients — In patients with PE who are hemodynamically unstable or who become unstable due to recurrence despite anticoagulation, we suggest more aggressive therapies (ie reperfusion therapies) than anticoagulation including the following (algorithm 1A-B):

Thrombolytic therapy is indicated in most patients, provided there is no contraindication (table 7) (see "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Hemodynamically unstable patients (high-risk pulmonary embolism)' and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Systemic infusion (full-dose thrombolytic)')

Embolectomy is appropriate for those in whom thrombolysis is either contraindicated or unsuccessful (surgical or catheter-based) (see 'Embolectomy' below)

Reperfusion therapy

Thrombolytic therapy — Systemic thrombolytic therapy is a widely accepted treatment for patients with PE who present with, or whose course is complicated by, hemodynamic instability. This therapy can be delivered more quickly than can be done via a catheter-based method; if there are no contraindications to systemic thrombolysis and the indication for reperfusion therapy is clear, the patient should not wait until an operator or catheterization service lab is available. Catheter-directed thrombus removal with or without thrombolysis can also be administered in select patients (eg, those at high risk of bleeding and those who have failed systemic thrombolysis). The indications, contraindications, agents, administration, and outcomes of systemic and catheter-directed thrombolysis are discussed separately. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration" and 'Catheter-directed modalities' below.)

For those in whom systemic thrombolysis is unsuccessful, the optimal therapy is unknown. Options include repeat systemic thrombolysis, catheter-directed thrombolysis, or catheter or surgical embolectomy, the choice of which is dependent upon available resources and local expertise. (See 'Embolectomy' below.)

Embolectomy — Embolectomy is indicated in patients with hemodynamically unstable PE in whom thrombolytic therapy is contraindicated. It is also a therapeutic option in those who fail thrombolysis. Emboli can be removed surgically or using a catheter. The choice between these options depends upon available expertise, the presence or absence of a known diagnosis of PE, underlying comorbidities, and the anticipated response to such therapies. As an example, when a patient has severe hemodynamic instability and standard dose thrombolysis is contraindicated, catheter-directed techniques may be preferred if the expertise is available. One advantage of this approach is that both diagnostic and therapeutic interventions can be applied simultaneously.

Catheter-directed modalities — Several catheter-directed techniques are available. Studies have been limited by small sample size and the inclusion of heterogeneous populations (patients who are hemodynamically stable and unstable, patients with and without contraindications to thrombolysis) as well as the adjunctive administration of catheter-directed thrombolytic agents. Nearly all modern-day catheter-directed thrombolysis trials have utilized tissue plasminogen activator (tPA). None has been demonstrated to have superiority over the other, such that the choice of technique is institution-dependent; an absolute contraindication to a thrombolytic agent means that if a catheter-directed technique is utilized, a catheter-directed clot extraction (ie, embolectomy) can be used. In our experience, catheter-directed techniques are most commonly utilized in patients with intermediate-high risk PE, although there is some experience with high-risk PE.

Options include:

Ultrasound-assisted thrombolysis – Catheter-directed high frequency ultrasound can enable the thrombolytic agent to better penetrate the embolus. Without thrombolytics, the technique has no proven benefit. This is the technique that is best supported by clinical trial data which are discussed separately. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Catheter-directed approaches' and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Catheter-directed thrombolytic therapy'.)

Rheolytic embolectomy – Rheolytic embolectomy injects pressurized saline through the catheter's distal tip while macerated thrombus is aspirated through a catheter port [57-62]. In a series of 16 patients with massive or submassive PE who underwent rheolytic embolectomy, resolution of symptoms and improvement in right ventricle dysfunction were achieved in all patients [61]. There were no in-hospital mortalities. Complications occurred in three patients (20 percent), two with acute kidney injury and one with an intraoperative cardiac arrest. Clinical success due to the intervention alone was unclear because two thirds of the cohort also received catheter-directed thrombolysis.

Because the catheter is large, the major disadvantage of rheolytic devices is that a venous cut-down (venotomy) is often required for insertion, which increases the risk of bleeding at the insertion site. In addition, the release of adenosine from disrupted platelets can lead to bradycardia, vasospasm, and hypoxia; similarly, red blood cell fragmentation can result in hemoglobinuria. These and other side effects have led to a boxed warning from regulatory agencies.

Rotational embolectomy – A rotating device at the catheter tip can be used to fragment the thrombus, while fragmented clot is continuously aspirated [63-67]. In a series of 18 patients with shock due to PE, clinical success was achieved in 16 cases (89 percent), defined as improvement in oxygenation and blood pressure. The remaining patients had complications (eg, hemorrhage) and one patient died from refractory shock [65]. Typically, rotational devices do not require venotomy.

Suction embolectomy – Thrombus can be manually aspirated through a large-lumen catheter using an aspiration syringe and a hemostatic valve [68,69]. In one study of 63 patients with mostly hemodynamically unstable PE who underwent suction embolectomy, 88 percent had a clinically significant reduction in clot burden and pulmonary artery pressure [69]. Six percent of patients died and 14 percent had major bleeding. Clinical success due to the intervention alone was unclear because all patients also received catheter-directed thrombolysis.

Technical difficulties with suction devices have limited their use but newer devices may be more successful [70-73]. As an example, in a study (FLARE), 106 patients with documented PE and RV dysfunction (ie, intermediate risk PE), aspiration thrombectomy with a newer device resulted in improvement in RV function and pulmonary artery pressure with a complication rate of only 4 percent [72]. There was one major bleed. Another retrospective study suggested improved in-hospital mortality and decreased ICU length of stay for patients with acute, central PE of elevated with a flow retrieval suction device [71].

More advanced catheters have been used for the removal of soft, fresh thrombi or for use during extracorporeal bypass. This applies most readily to large thromboemboli in the IVC, or right heart chambers. Such devices cannot easily access the pulmonary arteries to suction more distal emboli [74].

Thrombus fragmentation – Mechanical disruption of the thrombus can be achieved by manually rotating a standard pigtail or balloon angioplasty catheter into the thrombus; small fragments move distally and thereby result in reduced pulmonary vascular resistance [64,75,76]. While older studies report improved hemodynamic indices with fragmentation alone, newer studies have reported efficacy when fragmentation is combined with angioplasty, aspiration, and catheter-directed thrombolysis [77]. Although rare, catheter-fragmentation can increase pulmonary vascular pressures likely via embolization of larger fragments into the distal branches of the pulmonary vascular bed [78,79]. Consequently, aspiration of fragments is frequently concurrently performed to deal with this complication.

Common to all catheter-assisted embolectomy techniques is the risk of pulmonary artery perforation; although rare, it can lead to pericardial tamponade and life-threatening hemoptysis, and is frequently catastrophic. Additional complications include hemorrhage and infection of venipuncture sites, worsening hemodynamic instability, cardiac arrest, and death, as well as device-specific adverse effects (listed above). Hemorrhagic side effects can be exacerbated by the co-administration of thrombolytic therapy.

Surgical embolectomy — The usual indication for surgical embolectomy is hemodynamic instability due to acute PE for patients in whom thrombolysis (systemic or catheter-directed) is contraindicated, and is an option in those in whom thrombolysis has failed [80-83]. Additional indications may include echocardiographic evidence of an embolus trapped within a patent foramen ovale, or present in the right atrium, or right ventricle [84]. Surgical embolectomy is typically limited to large medical centers because an experienced surgeon and cardiopulmonary bypass are required. It has a high mortality, particularly in the older patient (2 to 46 percent) [80-83,85-93]. Proximal emboli are amenable to surgical removal (ie, right ventricle, main pulmonary artery [PA], and extrapulmonary branches of the PA), whereas distal thrombus generally is not amenable to surgery (eg, intrapulmonary branches of the PA).

In a retrospective database study, there was no difference in 30-day mortality with the 257 patients who underwent surgical embolectomy compared with 1854 patients with PE who underwent thrombolysis (15 versus 13 percent) [94]. In an observational study of 40 patients with PE who had failed systemic thrombolysis, patients who underwent surgical embolectomy had fewer recurrent PE compared with patients who had repeat thrombolysis (0 versus 35 percent) [86]. In addition, there were fewer deaths and fewer major bleeding complications associated with surgical embolectomy, which did not achieve statistical significance. In another series of 115 patients who underwent surgical embolectomy, compared with patients who had stable PE, those with unstable PE had a higher operative mortality (10 versus 4 percent) and worse survival (75 versus 93 percent) [90]. Another retrospective series reported an in hospital mortality of only 2 percent and immediate improvement of right ventricle pressures that persisted at 30 months [83].

Transesophageal echocardiography (TEE) should be performed before or during embolectomy to look for extrapulmonary thrombi (eg, in the right atrium, right ventricle, or vena cava). In a series of 50 patients with PE, intraoperative TEE detected extrapulmonary thrombi in 13 patients (26 percent), which altered the surgical management of five patients (10 percent) [95].

Cardiac arrest upon presentation predicts mortality from surgical embolectomy [80,96-99]. In one study of 36 patients with shock due to acute PE, but without cardiac arrest, the operative mortality associated with surgical embolectomy was 3 percent [97]. In contrast, operative mortality was 75 percent among patients with acute PE who were resuscitated from a cardiac arrest and then underwent surgical embolectomy [97,98].

Complications include those associated with cardiac surgery and anesthesia, as well as embolectomy-specific complications such as perforation of the pulmonary artery and cardiac arrest. (See "Postoperative complications among patients undergoing cardiac surgery".)

Special populations — In general, the initial approach to the treatment of PE as well as the treatment of life-threatening PE in special populations are similar to that in the general population (see 'Initial approach and resuscitation' above and 'Hemodynamically unstable patients' above). However, definitive therapy may differ in hemodynamically stable patients with malignancy, pregnancy, and heparin-induced thrombocytopenia.

Patients with malignancy — In hemodynamically stable patients with malignancy and PE, LMW heparin and some of the direct oral anticoagulants, edoxaban and apixaban, are used as anticoagulants. The details of supporting trials are discussed separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)

Patients who are pregnant — For most pregnant women with hemodynamically stable PE, adjusted-dose subcutaneous LMW heparin is the preferred agent for initial and long-term anticoagulation due to its favorable fetal safety profile (table 8). Treatment of PE in pregnancy is discussed in detail separately. (See "Use of anticoagulants during pregnancy and postpartum" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment".)

Patients with heparin-induced thrombocytopenia — For patients with PE and heparin-induced thrombocytopenia (HIT), all forms of heparin are contraindicated (eg, unfractionated and LMW heparin). Immediate anticoagulation with a fast-acting non heparin anticoagulant (eg, argatroban) is indicated. The diagnosis and management of patients with HIT are discussed in detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia".)

Inherited thrombophilias — In many cases, the presence of an inherited thrombophilia does not appreciably alter treatment decisions such as choice of an anticoagulant, but there may be specific circumstances in which the thrombophilia does affect management (eg, need for antithrombin [AT] administration in some individuals with AT deficiency). Details are presented in separate topic reviews:

Factor V Leiden – (See "Factor V Leiden and activated protein C resistance", section on 'Patients with VTE'.)

Prothrombin G20210A mutation – (See "Prothrombin G20210A", section on 'Patients with VTE'.)

Protein S deficiency – (See "Protein S deficiency", section on 'Patients with VTE'.)

Protein C deficiency – (See "Protein C deficiency", section on 'Thromboembolism management'.)

Antithrombin deficiency – (See "Antithrombin deficiency", section on 'VTE treatment (hereditary deficiency)'.)

Antiphospholipid syndrome — Considerations with treatment of VTE in patients with antiphospholipid syndrome (APS) are presented separately (eg, direct oral anticoagulants are generally not administered). (See "Management of antiphospholipid syndrome".)

ADJUNCTIVE THERAPIES — Therapies that can be added as an adjunct to anticoagulation in patients with pulmonary embolism (PE) are discussed in the sections below.

General medical — Patients with PE should always receive supportive care with analgesia, intravenous fluids, and oxygen, as clinically indicated (see 'Initial therapies' above). When present, pleuritic pain from PE is best treated with scheduled medications, usually acetaminophen or nonsteroidal antiinflammatories, and narcotics. The choice among these agents should be individualized. Failure to wean supportive therapies should prompt consideration of complications (eg, pneumonia or recurrence).

Ambulation — When feasible, early ambulation should be encouraged in most patients with acute PE, provided the patient is definitively treated. For those with significant clot burden and significant PE, bedrest may be needed for the first 12 to 24 hours to ensure therapeutic anticoagulation. Typically, ambulation is limited by the need for postoperative bedrest or by comorbidities including severe symptoms of concurrent deep venous thrombosis (DVT) or hypoxia . (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Ambulation'.)

Elastic graduated compression stockings — Elastic graduated compression stockings (GCS) are not routinely used in patients with DVT to prevent post-thrombotic syndrome (PTS). Detailed discussion of the manifestations and treatment of post-thrombotic syndrome (PTS) and role of GCS in the prevention of PTS are discussed separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Graduated compression stockings' and "Post-thrombotic (postphlebitic) syndrome".)

Inferior vena cava filters — In patients with acute PE, the primary indication for inferior vena cava (IVC) filter placement is when anticoagulation is contraindicated and when recurrent PE occurs despite therapeutic anticoagulation. However, it may be appropriate as an adjunct to anticoagulation in patients in whom another embolic event would be poorly tolerated (eg, poor cardiopulmonary reserve, or severe hemodynamic or respiratory compromise), although clinical data are lacking. Filters are not routinely placed as an adjunct in patients with PE. (See 'Management of recurrence on therapy' below.)

Filter placement is also sometimes used in patients with recurrence despite therapeutic anticoagulation or in those with a high risk of recurrence in whom it is anticipated that anticoagulation may need to be discontinued because of bleeding. Examples include patients at moderate risk of bleeding who cannot receive fresh frozen plasma or red cells (eg, due to religious preference), and patients with metastatic malignancy who are at a high risk for both recurrence and bleeding.

Although filters are not routinely placed as an adjunct in patients with PE, some experts place them in patients at risk of decompensation due to cardiorespiratory compromise. We agree that the adjunctive use of filters should not be routine, but placement may be individualized and should take into consideration the risk of recurrence and bleeding, patient preferences, institutional expertise, medical morbidities, and surgical complications.

IVC filter placement in patients with contraindications to anticoagulation and filter complications are reviewed separately. (See "Placement of vena cava filters and their complications".)

A femoral IV access line with a "built-in" IVC filter that can be opened when the line is placed and collapsed and removed when the line is removed has been found useful in high risk patients who cannot be treated with anticoagulants [100].

PROGNOSIS

Morbidity and mortality — Prognosis from pulmonary embolism (PE) is variable. Accurate estimates have been limited by data that are mostly derived from older studies, registries, and hospital discharge records collected from heterogeneous populations of patients. As an example, a patient with a single, asymptomatic, subsegmental pulmonary embolism (SSPE) likely has a different prognosis than a patient with massive PE and shock. However, in general, if left untreated, PE is associated with an overall mortality of up to 30 percent compared with 2 to 11 percent in those treated with anticoagulation [1,4,50,101-107]. PE-related mortality may be decreasing with reported rates falling from 3.3 percent (2001 to 2005) to 1.8 percent (2010 to 2013) in one study and from 17 to 10 percent in another study [107,108]. Another study that derived data from the World Health Organization (WHO) mortality database reported a similar decrease in deaths from 12.8 per 100,000 to 6.6 per 100,000 between 2000 and 2015 [109].

Early — We consider early outcomes as those occurring within the first three months after the diagnosis of PE. The highest risk for events occurs within the first seven days; death and morbidity during this period are most commonly due to shock and recurrent PE.

Shock (ie, hemodynamic collapse) – Shock can be the initial presentation or an early complication of PE (8 percent of patients). It is the most common cause of early death, particularly in the first seven days, and when present, is associated with a 30 to 50 percent risk of death [103,104,110]. The high risk of death, which is greatest in the first two hours of presentation, is the rationale for the consideration of reperfusion therapy (thrombolytics/embolectomy) rather than anticoagulation. The risk remains elevated for 72 hours or more, such that close observation of this population, as well as those considered at risk of hemodynamic collapse (eg, right ventricle dysfunction), is prudent during hospitalization. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration" and 'Embolectomy' above and 'Shock and right ventricular dysfunction' below.)

Recurrence – The risk of recurrence (deep venous thrombosis and PE) is greatest in the first two weeks, and declines thereafter. The cumulative proportion of patients with early recurrence while on anticoagulant therapy amounts to 2 percent at two weeks, and 6 percent at three months [111-113]. Factors including cancer and failure to rapidly achieve therapeutic levels of anticoagulation are major predictors of increased risk of recurrence during this period, the management of which is discussed below [114,115]. (See 'Management of recurrence on therapy' below.)

Pleuritic/alveolitis and pneumonia – In the one to two weeks following diagnosis, patients may deteriorate and develop worsening oxygenation, respiratory failure, hypotension, pain, and/or fever that suggests an evolving infarct and/or superimposed pneumonia. Although chest radiography may reveal collapse, atelectasis, or a pleural effusion to support the presence of an evolving infarct and/or superimposed pneumonia, these patients should undergo repeat definitive imaging (preferably with the original diagnostic imaging modality) to distinguish these diagnoses from recurrent PE. Patients without recurrence should be treated symptomatically with supplemental oxygen, analgesics, and intravenous fluids, and ventilation, vasopressors and/or antibiotics, as indicated.

Stroke – Prospective and retrospective studies have suggested an increased risk of stroke, thought to be due to paradoxical embolism via a patent foramen ovale (PFO), in patients with acute PE [116-120]. Prevalence rates of stroke have ranged from 7 to 50 percent (averaging <17 percent), with higher rates in those with PE who also have a PFO (21 to 64 percent, averaging <33 percent). Best illustrating this risk for stroke is a prospective study of 361 patients with acute PE who underwent contrast transthoracic echocardiography (TTE) and magnetic resonance imaging (MRI) of the brain (for silent or symptomatic stroke) within ten days after the diagnosis of PE [120]. Stroke was diagnosed in 7.6 percent and PFO in 13 percent of patients with acute PE. Rates of stroke were higher in those who had a PFO compared with those who did not have a PFO (21.4 versus 5.5 percent; relative risk 3.5, 95% CI 1.62-8.67). However, nine patients were excluded from the analysis due to inconclusive TTE or MRI testing and the rate of PFO was lower than that in the general population (approximately 25 to 30 percent) [121] suggesting that these results are flawed. Further studies are recommended before we can support a recommendation to routinely perform contrast echocardiography (transthoracic or transesophageal) or MRI imaging in patients with acute PE who have no symptoms of stroke. Accordingly, we prefer a symptom-directed approach such that vigilant surveillance for neurologic symptoms is appropriate in those with acute PE and the presence of stroke should prompt a search for a PFO. Whether the discovery of a PFO with PE and stroke should prompt indefinite anticoagulation and/or PFO closure is also unknown such that a multidisciplinary approach with a pulmonologist, neurologist, and cardiologist is prudent. Management of patients with stroke and PFO is discussed separately. (See "Patent foramen ovale" and "Initial assessment and management of acute stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

Late — The incidence of late events, at three months or later following a diagnosis of PE, ranges from 9 to 32 percent, with increased mortality reported for as long as 30 years [1,4,105,106,122,123]. Late mortality is mostly due to predisposing comorbidities, and less commonly due to recurrent thromboembolism or chronic thromboembolic pulmonary hypertension. As examples:

Mortality – In one retrospective study of 1023 patients with PE, the five-year cumulative mortality rate was 32 percent [123]. Among those who died, only 5 percent of the deaths were due to PE, 64 percent were due to non-cardiovascular causes (eg, malignancy, sepsis), and 31 percent were due to cardiovascular causes other than PE (eg, myocardial infarction, heart failure, and stroke). One year follow-up of patients in the prospective investigation of PE diagnosis (PIOPED) cohort revealed similar findings [1].

Another database analysis of over 128,000 patients with venous thromboembolism reported a three-fold increase in mortality at 30 years in patients with PE when compared with age and sex-matched controls who did not have PE during the same period [122].

Combined data from two prospective studies of 748 patients with PE reported that those with SSPE had similar rates of mortality (10 versus 7 percent) and recurrence (4 versus 3 percent) at three months when compared with patients with proximal PE [50]. Death in patients with SSPE was largely determined by comorbidities including malignancy, increasing age, male sex, chronic obstructive pulmonary disease, and heart failure.

Recurrence – The cumulative rate of late recurrence has been reported to be 8 percent at six months, 13 percent at one year, 23 percent at five years, and 30 percent at 10 years [111-113]. Rates of recurrence vary according to the population studied with comparable rates reported in those with SSPE and proximal PE at three months (4 versus 3 percent) [50]. However, in general, the rate is lowered with therapeutic anticoagulation, and increased by the presence of select risk factors (eg, unprovoked PE, malignancy), which are discussed separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Chronic thromboembolic disease (CTED) and chronic thromboembolic pulmonary hypertension (CTEPH) – CTED and CTEPH are unusual complications of PE that typically present with progressive dyspnea within two years of the initial event. The clinical manifestations and diagnosis of CTED and CTEPH are discussed separately. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

Other – PE has been associated with an increased risk for subsequent cardiovascular events and atrial fibrillation [124]. (See "Overview of the causes of venous thrombosis", section on 'VTE and atherosclerotic disease'.)

For most patients with dyspnea, exercise capacity and quality of life improve over the first year. Predictors of reduced improvement over time in one prospective study of 100 patients with acute PE were female sex, higher body mass index, prior lung disease, and higher systolic pulmonary artery pressure on day 10 echocardiography [125].

The likelihood of complications and death from PE may be differentially dependent upon the presence or absence of provoking risk factors at the time of diagnosis. A three-year observational study that followed 308 patients with PE found that patients with unprovoked PE were more likely to develop recurrence, CTEPH, malignancy, and cardiovascular events; in contrast, patients who had provoked PE had a higher risk of death over the seven-year study period [126].

Prognostic factors — Poor prognostic factors in patients diagnosed with PE are discussed in the sections below.

Shock and right ventricular dysfunction — Several clinical, radiologic, and laboratory markers of right ventricular (RV) dysfunction have been identified as poor prognosticators in patients with PE.

Clinical – The presence of clinical shock, which is due to severe RV failure, consistently predicts death in patients diagnosed with PE, the details of which are discussed above. (See 'Early' above.)

Radiologic (echocardiography and computed tomography pulmonary angiography [CTPA]) – RV dysfunction assessed by echocardiography or CT pulmonary angiography (CTPA), is associated with increased mortality [127-133], although we believe that echocardiography is more reliable than CTPA.

One meta-analysis of seven studies that included 3395 normotensive and hypotensive patients with PE reported that RV dysfunction was associated with a two-fold increase in PE-related in-hospital mortality [133]. However, a subgroup analysis of normotensive patients found that RV dysfunction on echocardiography or CT correlated poorly with mortality, suggesting that it is symptomatic RV dysfunction that predicts death.

In a study of 1950 patients diagnosed and treated with PE in a prospective multicenter trial, larger pulmonary trunk diameter on CTPE was associated with higher mortality during the treatment period of 3 to 6 months (OR 2.8, 95% CI 1.3-5.7) and at one year (OR 2.3, 95% CI 1.4-4.0) [134]. An association with right ventricular dysfunction was not observed.

RV dysfunction may also predict recurrent venous thromboembolism (VTE). In one prospective observational study of 301 patients with PE, those with persistent RV dysfunction on echocardiography at three months following diagnosis had a four-fold increased risk of recurrent VTE when compared with patients without RV dysfunction or with patients whose RV dysfunction resolved prior to discharge (9 versus 3 and 1 percent patient-years) [135].

Echocardiographic findings of RV dysfunction in patients with PE are discussed separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Echocardiography' and "Echocardiographic assessment of the right heart", section on 'Conditions associated with right ventricular pathology'.)

Laboratory markers – Biochemical markers of RV dysfunction at diagnosis include elevated levels of the following:

Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) from RV strain

Troponin-I and T levels due to RV-associated myocardial damage

In general, elevated BNP, NT-proBNP, and troponin have consistently been associated with an increased risk of death or other adverse outcomes in patients with PE [127,136-145]. However, the optimal cut-off values for risk stratification are unknown. In hemodynamically stable patients, these markers are poor predictors of death when elevated but consistently identify a benign clinical course when normal or low [129,137,140,141,143,145-148].

BNP and NT-proBNP as biomarkers of left heart failure and the differential diagnosis of elevated troponins, other than acute coronary syndrome, are discussed in detail separately. (See "Natriuretic peptide measurement in heart failure" and "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome".)

Right ventricle thrombus — Mobile right heart thrombi are seen in approximately 4 percent of patients with PE, by either echocardiography or CT, and the proportion is higher among patients who are critically ill (up to 18 percent) [149,150]. The presence of right heart thrombus has been shown in several studies to be associated with RV dysfunction and high early mortality [149,151,152]. As an example, data from an international registry of patients with PE reported that, compared with patients without RV thrombus, patients with RV thrombus had a higher 14-day mortality (21 versus 11 percent) and three-month mortality (29 versus 16 percent) [149].

Deep vein thrombosis — Patients with PE and a coexisting deep vein thrombosis (DVT) are at increased risk for death. As an example, one prospective study of 707 patients with PE reported increased all-cause mortality (adjusted hazard ratio [HR] 2.05, 95% CI 1.24-3.38) and PE-specific mortality (adjusted HR 4.25, 95% CI 1.61-11.25) at three months in patients with concomitant DVT compared with those without concomitant DVT [32].

Other — Additional predictors of poor prognosis that require further validation include the following:

Hyponatremia (<130 mmol/L) and indicators of renal dysfunction [153-155]

Serum lactate (>2 mmol/L) [156,157]

White blood cell count (>12.6 x 109/L) [158]

The Charlson co-morbidity index ≥1 [159]

Residual pulmonary vascular obstruction [160,161]

Older age ≥65 years [162]

Right heart thrombus [163,164]

Poor adherence to guidelines [165]

Tachycardia on admission [166]

Prognostic models — Prognostic models can facilitate the decision to treat patients as an outpatient and identify those that require vigilant monitoring as an inpatient. Their role in management outside of this context is unclear. (See 'Outpatient anticoagulation' above.)

Several prognostic models have been derived in patients with acute PE, of which the Pulmonary Embolism Severity Index (PESI) and the simplified PESI (sPESI) are the most well known (table 6) [167-171]. While PESI and sPESI predict death, newer composite models predict death and/or complications (recurrent PE, hemodynamic collapse). As examples:

PESI – The PESI adds the patient's age to points assigned to ten additional variables (table 6) [167]: male sex (+10 points), history of cancer (+30 points), heart failure (+10 points), chronic lung disease (+10 points), pulse ≥110 beats per minute (+20 points), systolic blood pressure <100 mmHg (+30 points), respiratory rate ≥30 breaths per minute (+20 points), temperature <36 degrees C (+20 points), altered mental status (+60 points), and arterial oxygen saturation <90 percent (+20 points). The total score categorizes the patient according to increasing risk for mortality:

Class I (<66 points)

Class II (66 to 85 points)

Class III (86 to 105 points)

Class IV (106 to 125 points)

Class V (>125 points)

Patients with class I/II are considered to be at low risk of death, compared with classes III through V, who are at high risk. The major limitation of the PESI is that it is difficult to apply in a busy clinical setting because so many variables must be considered, each with its own weight.

sPESI – The sPESI assigns one point for each of the following variables: age >80 years, a history of cancer, chronic cardiopulmonary disease, a heart rate ≥110 beats per minute, a systolic blood pressure <100 mmHg, and an arterial oxyhemoglobin saturation <90 percent [172]. A score of zero indicates a low risk for mortality, while a score of one or more indicates a high risk.

The sPESI may have a prognostic accuracy that is similar to PESI. In a cohort of 995 patients with PE that compared PESI with sPESI, a similar 30-day mortality was reported in patients classified as low risk (3 versus 1 percent ) or high risk (11 percent each) [172]. Prospective validation of the sPESI is needed.

Other – A composite model that incorporates sPESI, brain natriuretic peptide (BNP), cardiac troponin I, and lower limb ultrasound (done within 48 hours of admission) was derived and validated in a cohort of 848 normotensive patients with acute PE [170]. The combination of a low risk sPESI score and BNP <100 pg/mL identified patients at low risk of death, hemodynamic collapse, and/or recurrent PE at 30 days (negative predictive value of 99 to 100 percent). The combination of high risk sPESI, elevated BNP, elevated troponin I, and concomitant deep venous thrombosis identified patients who were at high risk of death or complications at 30 days (positive predictive value, 21 to 26 percent). Further validation of this model is required before it can be routinely applied in clinical practice.

While many of the available prognostic models are sensitive in predicting death from acute PE, they are not specific. One study of 11 clinical prognostic models reported that although the sensitivity of some models, including PESI and sPESI, were >89 percent, none had a specificity greater than 48 percent [173].

MONITORING AND FOLLOW-UP — Patients with pulmonary embolism (PE) should be monitored following diagnosis for the following:

Therapeutic levels of anticoagulation in patients receiving heparin and warfarin – The most common laboratory test used to monitor unfractionated heparin is the activated partial thromboplastin time (aPTT) with a target range of 1.5 to 2.5 times the upper limit of normal. Some experts monitor heparin levels. Warfarin is monitored using the prothrombin time (PT) ratio usually expressed as the international normalized ratio (INR) with a goal INR of 2 to 3 (target 2.5). (See "Biology of warfarin and modulators of INR control".)

Low molecular weight heparin, fondaparinux, and the factor Xa and direct thrombin inhibitors do not require routine laboratory monitoring. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

The development of conditions that affect the half-life of the anticoagulant used (eg, renal failure, pregnancy, weight gain/loss, drug interactions) should also be followed.

Early complications of PE, predominantly recurrence – In the one to two weeks following diagnosis, patients may deteriorate and experience recurrence, the management of which is discussed below. (See 'Management of recurrence on therapy' below.)

Whether patients should undergo echocardiography (transthoracic or transesophageal) or MRI of the brain to look for a patent foramen ovale (PFO) or asymptomatic stroke is unclear. However, symptom-driven evaluation for a PFO and stroke is appropriate.

Late complications of PE including recurrence and chronic thromboembolic disease (CTED) and chronic thromboembolic pulmonary hypertension (CTEPH) – At each visit, patients should be monitored for continued resolution of the presenting manifestations of PE and investigated for new symptoms suggestive of recurrent PE or deep venous thrombosis [174]. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

The development of persistent or progressive dyspnea, particularly during the first three months to two years of diagnosis, should prompt the clinician to investigate for the development of CTEPH (affects up to 5 percent of patients). While some clinicians do not routinely perform follow-up computed tomography, ventilation perfusion scans, or echocardiography, clinicians should have a low threshold to repeat diagnostic imaging if recurrence or CTEPH is suggested. In addition, some experts evaluate for CTEPH in those with risk factors. The risks, clinical manifestations and diagnosis of CTEPH are discussed separately. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

Complications of the therapy itself including bleeding and adverse effects of medications or devices – Patients should be monitored for complications including bleeding (anticoagulants), skin necrosis (warfarin), osteoporosis (heparin), thrombocytopenia (heparin), and device migration (caval filters). Details regarding the individual complications of such therapies are discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects" and "Warfarin and other VKAs: Dosing and adverse effects" and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects" and "Placement of vena cava filters and their complications", section on 'Complications' and 'Embolectomy' above and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Efficacy'.)

The risk of recurrence and bleeding – The risk of recurrence and bleeding should be periodically reassessed in patients during and upon completion of therapy to assess the ongoing need for such treatment. As an example, patients with major bleeding while on anticoagulation should not continue, whereas those with minor bleeding (eg, epistaxis) or recurrence should continue to be anticoagulated. The indications for indefinite anticoagulation are discussed separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

The need for device removal – Patients who had an inferior vena cava filter placed because anticoagulation was contraindicated should, once the contraindication has resolved, initiate anticoagulant therapy and have the filter retrieved, if feasible. (See "Placement of vena cava filters and their complications", section on 'Filter retrieval'.)

The underlying predisposing risk factors for PE – The presence or absence of risk factors that predisposed the patient to the development of PE (eg, malignancy, inherited thrombotic disorder, surgery) should be sought and investigated, as indicated. The evaluation of patients with established venous thromboembolism for risk factors is discussed separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

In some institutions, specialty clinics follow patients with PE (eg, "clot clinic") to ensure adequate and thorough follow-up, although the benefits of such clinics are unknown.

MANAGEMENT OF RECURRENCE ON THERAPY — Inadequate anticoagulation is the most common reason for recurrent venous thromboembolism (VTE; PE and/or deep venous thrombosis) while on therapy. Explanations for subtherapeutic anticoagulation as well as several additional etiologies for recurrence that should be considered are listed below:

Subtherapeutic anticoagulation – Subtherapeutic anticoagulation is the most common reason for recurrence. A detailed history and examination should be performed to identify factors that contribute to subtherapeutic anticoagulation. These include:

Malabsorption (eg, malabsorption syndromes, rivaroxaban should be taken with food) (see "Overview of nutrient absorption and etiopathogenesis of malabsorption")

Discontinuation for an anticipated procedure (see "Perioperative management of patients receiving anticoagulants")

Poor compliance

Altered dose requirement or pharmacokinetics for warfarin (eg, dietary vitamin K), target-specific oral anticoagulants (eg, drug interactions), or low molecular weight heparin (low molecular weight [LMW] heparin; eg, weight gain)

High dose requirement for heparin (eg, increased heparin binding proteins, aprotinin)

Incorrect dosing of medication

Consulting a coagulation specialist may be warranted, especially when abnormal pharmacokinetics or noncompliance for medications that cannot be monitored easily (eg, target-specific oral anticoagulants, LMW heparin) are suspected. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Heparin resistance/antithrombin deficiency' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects" and "Biology of warfarin and modulators of INR control".)

For those subtherapeutic on unfractionated heparin, the dose should be increased to rapidly achieve therapeutic levels. For patients who are on low molecular weight heparin or factor Xa and direct thrombin inhibitors in whom subtherapeutic anticoagulation is suspected but unconfirmed, or for those subtherapeutic on warfarin, switching to a rapid–acting anticoagulant that can be followed (eg, unfractionated heparin) may be prudent while investigations are ongoing.

Because new direct thrombin and Xa inhibitors do not require monitoring, it is yet to be determined whether challenges will emerge with monitoring for therapeutic levels.

Suboptimal therapy – Therapeutic anticoagulation is the optimal therapy for VTE. Suboptimal therapies, including inferior vena cava filters and embolectomy or thrombolysis not followed by anticoagulation, should be apparent to the investigating clinician. Resumption of therapeutic anticoagulation should be considered in such cases, when feasible.

Ongoing prothrombotic stimuli – In patients who develop recurrence despite therapeutic anticoagulation, a search for conditions associated with high recurrence rates is prudent. These include malignancy, May-Thurner syndrome, inherited thrombotic disorders (eg, protein S, protein C, or antithrombin deficiency), and antiphospholipid syndrome. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Overview of the causes of venous thrombosis", section on 'Anatomic risk factors for deep venous thrombosis'.)

In this population, therapeutic options are limited. We suggest an approach similar to that performed in patients with recurrent thrombosis who have an underlying malignancy. These options include treatment with an LMW heparin for those on warfarin, escalation of the dose of LMW heparin for those on LMW heparin, and/or the addition of a vena cava filter. The efficacy of factor Xa and direct thrombin inhibitors in this population is unstudied. Further details regarding these strategies are discussed separately. (See "Management of antiphospholipid syndrome", section on 'Recurrent thromboembolism despite adequate anticoagulation' and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Management of recurrence'.)

Recurrence may also be associated with conditions that promote thrombus propagation (eg, mechanical obstruction of venous flow from pelvic masses or inferior vena cava filter), or thrombus dissociation (eg, large right ventricular [163] or valvular thrombus). In such patients, treating the underlying cause or removing mobile thrombus may be appropriate, when feasible.

Misdiagnosis – Occasionally, tumor or fat emboli may radiographically mimic PE due to thrombus, the presentation and management of which are discussed separately. (See "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management" and "Fat embolism syndrome".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Pulmonary embolism (blood clot in the lungs) (The Basics)")

Beyond the Basics topics (see "Patient education: Pulmonary embolism (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Initial resuscitation – The initial approach to patients with suspected pulmonary embolism (PE) should focus upon stabilizing the patient while clinical evaluation and definitive diagnostic testing is ongoing (algorithm 1A-B). (See 'Initial approach and resuscitation' above and 'Initial therapies' above.)

Respiratory and hemodynamic support (see 'Respiratory support' above and 'Hemodynamic support' above):

-Supplemental oxygen should be administered to target an oxygen saturation ≥90 percent.

-Severe hypoxemia, hemodynamic collapse, or respiratory failure should prompt consideration of mechanical ventilation. When mechanical ventilation is necessary, we prefer that an expert in cardiovascular anesthesia be consulted, when feasible, to avoid catastrophic hypotension due to sedation and positive pressure ventilation.

-For those who require hemodynamic support, we suggest cautious infusions of intravenous fluid (IVF; 500 to 1000 mL of normal saline) rather than larger volumes (Grade 2C). Vasopressor therapy should be initiated if perfusion fails to respond to IVF.

Empiric anticoagulation – For patients with suspected PE who are hemodynamically stable or hemodynamically unstable and successfully resuscitated, the administration of empiric anticoagulation depends upon the risk of bleeding (table 3), the clinical suspicion for PE ((table 2) (calculator 1)), and the expected timing of diagnostic tests (see 'Hemodynamically stable' above and 'Empiric anticoagulation' above) (related Pathway(s): Pulmonary embolism (confirmed or suspected): Initial management of hemodynamically stable adults):

-For patients with a low risk of bleeding and a high clinical suspicion for PE, we suggest empiric anticoagulation rather than waiting until definitive diagnostic tests are completed (Grade 2C). We use a similar approach in those with a moderate or low clinical suspicion for PE in whom the diagnostic evaluation is expected to take longer than four hours and 24 hours, respectively.

-We do not anticoagulate patients with absolute contraindications to anticoagulant therapy or those with an unacceptably high risk of bleeding (Grade 1C).

-For patients with a moderate risk of bleeding, empiric anticoagulant therapy may be administered on a case-by-case basis according to the assessed risk-benefit ratio (table 3).

-The optimal agent for empiric anticoagulation depends upon hemodynamic instability, the anticipated need for procedures or thrombolysis, and the presence of risk factors and comorbidities.

Definitive therapy for suspected PE – For those with suspected PE, we perform the following:

In patients with a high clinical suspicion for PE who are hemodynamically unstable and who have a definitive diagnosis by portable perfusion scanning or a presumptive diagnosis of PE by bedside echocardiography (because definitive diagnostic testing is unsafe or not feasible), we suggest systemic thrombolytic therapy rather than empiric anticoagulation or no therapy (Grade 2C). (See 'Hemodynamically unstable' above.) (Related Pathway(s): Pulmonary embolism (confirmed or suspected): Initial management of hemodynamically unstable adults.)

If bedside testing is delayed or unavailable, the use of thrombolytic therapy as a life-saving measure should be individualized; if not used, the patient should receive empiric anticoagulation.

For patients who are hemodynamically unstable and the clinical suspicion is low or moderate, we suggest empiric anticoagulation similar to that suggested for patients who are hemodynamically stable; empiric thrombolysis is not justified in this population.

The employment of a multidisciplinary team may be of value in patients who are unstable due to PE or in select patients with intermediate to high-risk PE.

Definitive therapy for confirmed PE – For patients in whom the diagnostic evaluation confirms PE, we suggest an approach that is stratified according to whether or not the patient is hemodynamically stable or unstable (algorithm 1A-B). At any time, the strategy may need to be redirected as complications of PE or therapy arise. (See 'Definitive therapy' above.)

Hemodynamically stable low-risk/nonmassive PE – For most hemodynamically stable patients with PE that is low risk/nonmassive, the following applies (see 'Hemodynamically stable patients' above):

-For those in whom the risk of bleeding is low, we recommend that anticoagulant therapy be initiated or continued (Grade 1B) (table 4). (See 'Anticoagulation' above.)

-Outpatient anticoagulation is safe and effective in select patients at low risk of death (table 6), provided that they do not have respiratory distress, serious comorbidities, or requirement for oxygen or narcotics, and that they also have a good understanding of the risks and benefits of such an approach. (See 'Outpatient anticoagulation' above.)

-Most patients with subsegmental PE should be anticoagulated; however, in a small select population, observation with serial lower extremity ultrasonography may be appropriate. (See 'Patients with subsegmental PE' above.)

-For those who have contraindications to anticoagulation or have an unacceptably high bleeding risk (table 3), we suggest that an inferior vena cava (IVC) filter be placed rather than observation (Grade 2C). (See 'Inferior vena cava filter' above.)

-For those in whom the risk of bleeding is moderate, therapy should be individualized according to the risk-benefit ratio and preferences of the patient.

-In most hemodynamically stable patients, we recommend against thrombolytic therapy (Grade 1C).

Hemodynamically stable intermediate-risk/submassive PE – For most hemodynamically stable (ie, normotensive) patients with intermediate-risk/submassive PE, anticoagulation should be administered and patients monitored closely for deterioration. Examples of such patients include those who subsequently deteriorate due to recurrent PE, have a large clot burden, severe RV enlargement/dysfunction, have high oxygen requirement, and/or severely tachycardic (table 5). Thrombolysis and/or catheter-based therapies may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of hemorrhage (eg, deterioration due to PE). (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration".)

Hemodynamically unstable PE – For most patients with hemodynamically unstable PE, the following applies (see 'Hemodynamically unstable patients' above):

-No contraindications to thrombolysis – For patients with refractory hypotension and without contraindications to thrombolysis (table 7), we suggest systemic thrombolytic therapy followed by anticoagulation rather than anticoagulation alone (Grade 2C) (table 5). We suggest a similar approach for select patients whose course becomes complicated by hypotension during anticoagulation in whom the suspicion for recurrent PE despite anticoagulation is high. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration" and 'Thrombolytic therapy' above.)

-Contraindications to thrombolysis – For those in whom thrombolysis is contraindicated (table 7), we suggest catheter or surgical embolectomy rather than observation (Grade 2C). The choice between these options depends upon a variety of factors. (See 'Embolectomy' above.)

-Failed thrombolysis – For those in whom systemic thrombolysis is unsuccessful, the optimal therapy is unknown. Options include repeat systemic thrombolysis, catheter-directed thrombolysis, or catheter or surgical embolectomy. Our preference is for catheter-based thrombolysis. However, in many cases, the choice is dependent upon available resources and local expertise. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Hemodynamically unstable patients (high-risk pulmonary embolism)'.)

Adjunctive therapies – In patients with PE who are fully anticoagulated, we suggest early ambulation rather than bedrest, when feasible (Grade 2C). Although, IVC filters are not routinely used adjunctively in patients who are therapeutically anticoagulated, they are used in rare circumstances by some experts (eg, those with poor cardiorespiratory reserve), although this strategy is largely unproven. (See 'Adjunctive therapies' above.)

Prognosis – PE, left untreated, has a mortality of up to 30 percent, which is significantly reduced with anticoagulation. The highest risk occurs within the first seven days, with death most commonly due to shock. Prognostic models that incorporate clinical findings (eg, Pulmonary Embolism Severity Index [PESI] and the simplified PESI [sPESI] (table 6)) and/or biochemical markers that indicate right ventricle strain (natriuretic peptides, troponin) can predict early death and/or recurrence. (See 'Prognosis' above.)

Follow-up – Patients treated with unfractionated heparin and/or warfarin should be monitored for laboratory evidence of therapeutic efficacy. Patients should also be monitored for early (eg, recurrence) and late (eg, chronic thromboembolic pulmonary hypertension) complications of PE, as well as for the complications of anticoagulation and other definitive therapies. In addition, patients should be investigated for the underlying cause of PE. (See 'Monitoring and follow-up' above.)

Management of recurrence – Inadequate anticoagulation is the most common reason for recurrent venous thromboembolism while on therapy. The clinician should test for therapeutic levels of anticoagulants when relevant as well as considering additional etiologies of recurrence (eg, suboptimal therapy, ongoing prothrombotic stimuli, and alternate diagnoses). (See 'Management of recurrence on therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Victor F Tapson, MD, who contributed to earlier versions of this topic review.

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Topic 8265 Version 97.0

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