Disclosures: Victor F Tapson, MD Grant/Research/Clinical Trial Support: Janssen [VTE prophylaxis (Rivaroxaban)]; EKOS (BTG) [VTE treatment (Ultrasound assisted thrombolysis in acute PE)]; Portola [VTE prophylaxis (Betrixaban)]. Speaker’s Bureau Janssen [VTE treatment (Rivaroxaban)]. Consultant/Advisory Boards: AngioDynamics [VTE treatment (AngioVac)]; EKOS (BTG) [VTE treatment (Ultrasound assisted thrombolysis in acute PE)]; Daiichi [VTE treatment (Edoxaban)]; Janssen [VTE treatment (Rivaroxaban)]; Portola [VTE prophylaxis (Betrixaban)]. Jess Mandel, MD Nothing to disclose. Robert S Hockberger, MD, FACEP Nothing to disclose. Geraldine Finlay, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Acute pulmonary embolism (PE) is a common and sometimes fatal disease with a highly 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 adult with suspected acute pulmonary embolism" and "Anticoagulation in acute pulmonary embolism" and "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis".)
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. 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 (“massive” PE) is that which presents with hypotension; hypotension is defined as a systolic blood pressure (BP) <90 mmHg for a period >15 minutes, hypotension requiring vasopressors, or clear evidence of shock.
●Hemodynamically stable PE is defined as PE that does not meet the definition of hemodynamically unstable PE. These patients are a heterogeneous group ranging from patients with small PE and stable BP (“low risk”) to patients with larger PE who have right ventricular dysfunction and borderline BP (ie, “submassive” PE/intermediate risk).
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 . 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 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, “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 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 therapies. (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 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 an interventional procedure. Thus, when feasible, it is prudent to adopt a multidisciplinary approach to facilitate management of hemodynamically unstable patients with PE; some centers have incorporated a “pulmonary embolism response team” (PERT) to facilitate the process .
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 adult with suspected acute pulmonary embolism", section on 'Echocardiography' and "Clinical presentation, evaluation, and diagnosis of the adult with suspected acute pulmonary embolism", section on 'Hemodynamically unstable patients' and "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Hemodynamically unstable patients' and 'Embolectomy' below.)
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 "Sedation or induction agents for rapid sequence intubation in adults" and "Direct laryngoscopy and tracheal intubation in adults" and "Overview of mechanical ventilation", section on 'Initiation' and "Extracorporeal membrane oxygenation (ECMO) in adults".)
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 [8-12]. 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.
●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) [9,13-15]. Options include:
•Norepinephrine – Norepinephrine is the most frequently utilized agent in this population because it is effective and less likely to cause tachycardia . Other alternatives include dopamine and epinephrine, but tachycardia, which can exacerbate hypotension, can occur with these agents .
•Dobutamine – Dobutamine 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 [14,15]. To mitigate this effect, we 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 are not useful for hypotension due to acute PE [16,17]. 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 [5,12]. 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 adult with suspected acute pulmonary embolism", section on 'Determining the clinical probability of pulmonary embolism' and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", 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 should be considered in the following patient groups:
•A high clinical suspicion for PE (ie, Wells score >6)
•A moderate clinical suspicion for PE (ie, Wells score 2 to 6), in whom the diagnostic evaluation is expected to take longer than four hours
•A low clinical suspicion for PE (ie, 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 physician 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. As an example, low molecular weight heparin (LMWH) 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). In contrast, unfractionated heparin is preferred by most experts in patients who are hemodynamically unstable in anticipation of a potential need for thrombolysis or embolectomy. Direct thrombin and factor Xa inhibitors should not be used in hemodynamically unstable patients. (See "Anticoagulation in acute pulmonary embolism", section on 'Initiation of anticoagulant therapy'.)
Our approach — For patients in whom the diagnostic evaluation excludes pulmonary embolism (PE) (see "Clinical presentation, evaluation, and diagnosis of the 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.)
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 submassive PE (moderate/intermediate risk), and minor PE (low risk).
We suggest the following approach for most hemodynamically stable (ie, normotensive) patients with minor/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.)
●For most hemodynamically stable patients, we recommend against thrombolytic therapy (eg, low risk patients).
For hemodynamically stable (ie, normotensive) patients with intermediate-risk/submassive PE, therapy should be individualized. 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 4). The details of such therapies are discussed separately. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Hemodynamically stable patients' and "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Administration'.)
Anticoagulation — Anticoagulant therapy is indicated for patients with PE in whom the risk of bleeding is low:
●Initial anticoagulation (0 to 10 days) – Initial anticoagulant therapy is administered as soon as possible in order to quickly achieve therapeutic anticoagulation. A detailed discussion of agent selection and patient selection for outpatient anticoagulation is presented separately. (See "Anticoagulation in acute pulmonary embolism", section on 'Initiation of anticoagulant therapy' and "Lower extremity deep venous thrombosis: Initiation of anticoagulation (first 10 days)" and 'Outpatient anticoagulation' below.)
●Long-term anticoagulation (10 days to three months) – Long-term anticoagulant therapy is administered beyond the initial phase of anticoagulation for a finite period of typically three months (eg, transient VTE risk factors), or up to 6 or 12 months in some cases (eg, persisting risk factors, or unprovoked VTE). Agent selection and duration of long-term anticoagulation in patients with PE and deep venous thrombosis (DVT) are discussed in detail separately. (See "Anticoagulation in acute pulmonary embolism", section on 'Choice of agents' and "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)".)
●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). The rationale and indications for indefinite anticoagulation are described separately. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism".)
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, several randomized trials and meta-analyses suggest that, in patients with PE, outpatient anticoagulation is safe and effective in those with the all of the following features [5,18-26]:
●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 LMWH chosen), and have good home support (eg, do not live alone, have access to a telephone and physician, 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 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 [22,24,26]. As examples:
●One open label, multicenter trial randomly assigned 344 patients with symptomatic PE and a low risk of death (PESI I/II; (table 5)) to receive either inpatient (intravenous heparin followed by warfarin) or outpatient (subcutaneous low molecular weight heparin followed by warfarin) therapy . 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 . 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.
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 lower extremity deep vein thrombosis (DVT)", section on 'Outpatient therapy'.)
Patients with incidental and small subsegmental PE — The increasing use of computed tomography (CT) has led to the increased diagnosis of incidental (asymptomatic) PE and small subsegmental PE (SSPE) the clinical relevance of which is uncertain. One observational study reported that 15 percent of patients with PE have SSPE . As an example, a single subsegmental defect probably does not have the same clinical relevance as a single segmental or lobar PE or multiple SSPE.
The optimal therapy for SSPE is unknown. Observational data suggest that some clinicians elect not to anticoagulate patients with SSPE, especially if an alternate etiology is discovered on CT . However, most experts believe that, when found, such patients should be treated in a similar fashion to patients with symptomatic or large lobar defects . This is particularly important when risk factors for VTE, such as cancer, persist, and when there is concomitant DVT. The duration of anticoagulation in such cases should be individualized, the details of which are discussed separately. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Unprovoked incidental PE' and "Anticoagulation in acute pulmonary embolism", section on 'Duration of therapy'.)
Inferior vena cava filter — For most patients with PE in whom anticoagulation is contraindicated, or patients in whom the risk of bleeding is unacceptably high, an inferior vena cava (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. Retrievable filters are preferred, 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, and use as an adjunct to anticoagulation are presented separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Inferior vena cava filter' and "Placement of vena cava filters and their complications" and 'Inferior vena cava filters' below.)
When contraindications to anticoagulation are present, 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 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.
Hemodynamically unstable patients — In patients with PE who are hemodynamically unstable we suggest more aggressive therapies including the following (algorithm 1A-B):
●Thrombolytic therapy is indicated in most patients, provided there is no contraindication (table 6) (see "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Hemodynamically unstable patients' and "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Administration')
●Embolectomy is appropriate for those in whom thrombolysis is either contraindicated or unsuccessful (surgical or catheter-based) (see 'Embolectomy' below)
Thrombolytic therapy — Systemic thrombolytic therapy is a widely accepted indication for patients with PE who present with, or whose course is complicated by, hemodynamic instability. Thrombolytic agents can also be administered via a catheter. The indications, contraindications, agents, administration, and outcomes of systemic and catheter-directed thrombolysis are discussed separately. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis".)
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, 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 agent. None has been demonstrated to have superiority over the other, such that the choice of technique is institution-dependent. Although the combination of catheter-based embolectomy and thrombolysis is considered investigational, in our experience, catheter-directed techniques are most commonly utilized in patients with moderate/intermediate risk PE, although there is some experience with massive PE.
●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. The use of ultrasound-assisted thrombolysis was best demonstrated in one randomized study of hemodynamically stable patients with PE in conjunction with low-dose thrombolytic agent (ULTIMA), the details of which are discussed separately. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Catheter-directed'.)
●Rheolytic embolectomy – Rheolytic embolectomy injects pressurized saline through the catheter's distal tip while macerated thrombus is aspirated through a catheter port [28-33]. 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 . 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 [34-38]. 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 . 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 [39,40]. 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 . 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 .
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 .
●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 [35,43,44]. 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 . Although rare, catheter-fragmentation can increase pulmonary vascular pressures likely via embolization of larger fragments into the distal branches of the pulmonary vascular bed [46,47]. 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, 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. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Catheter-directed'.)
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 [48-50]. Additional indications may include echocardiographic evidence of an embolus trapped within a patent foramen ovale, or present in the right atrium, or right ventricle . 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 elderly (6 to 46 percent) [48-50,52-56]. 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 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) . In addition, there were fewer deaths and fewer major bleeding complications associated with surgical embolectomy, which did not achieve statistical significance.
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) .
Cardiac arrest upon presentation predicts mortality from surgical embolectomy [48,58-61]. 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 . In contrast, operative mortality was 75 percent among patients with acute PE who were resuscitated from a cardiac arrest and then underwent surgical embolectomy [59,60].
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, low molecular weight heparin (LMWH) is the preferred agent for all phases of anticoagulation, the details of which are discussed separately. (See "Treatment of venous thromboembolism in patients with malignancy".)
Patients who are pregnant — For most pregnant women with hemodynamically stable PE, adjusted-dose subcutaneous LMWH is the preferred agent for initial and long-term anticoagulation due to its favorable fetal safety profile (table 7). 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 LMWH). 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".)
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 — Early ambulation does not promote embolization and, when feasible, should be encouraged in most patients with acute PE, once the patient is definitively treated. Typically, ambulation is limited by the need for postoperative bedrest, or by comorbidities including severe symptoms of concurrent deep venous thrombosis (DVT) or hypoxia, which can be treated with compression stockings and oxygen, respectively. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Ambulation'.)
Elastic graduated compression stockings — Elastic graduated compression stockings (GCS) are used in patients with DVT to prevent post-thrombotic syndrome (PTS). Thus, GCS are unlikely to be of value in those with PE unless DVT is also present. The use of GCS in patients with DVT and the manifestations and treatment of PTS are discussed separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Compression stockings for the prevention of PTS' and "Post-thrombotic (postphlebitic) syndrome".)
Inferior vena cava filters — 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. (See 'Management of recurrence on therapy' below.)
Filter placement is also sometimes used in patients 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.
The adjunctive use of filters should be individualized and 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 is being studied for high risk patients who cannot be treated with anticoagulants .
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 [1,4,63-69].
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 [65,66,70]. 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 "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis" 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 [71-73]. 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 [74,75]. (See 'Management of recurrence on therapy' below.)
●Other – Additional complications of acute PE that may also contribute to early morbidity include pleuritis/alveolitis from an evolving pulmonary infarction and superimposed pneumonia, the management of which is discussed below. (See 'Monitoring and follow-up' below.)
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 [1,4,67,68,76,77]. 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 . 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 .
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 .
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 . Death in patients with SSPE was largely determined by comorbidities including malignancy, increasing age, male gender, 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 [71-73]. 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) . 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 "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Assessing the risk of recurrence'.)
●Chronic thromboembolic pulmonary hypertension (CTEPH) – CTEPH is an unusual complication of PE that typically presents with progressive dyspnea within two years of the initial event. The clinical manifestations and diagnosis of CTEPH are discussed separately. (See "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 . (See "Overview of the causes of venous thrombosis", section on 'VTE and atherosclerotic disease'.)
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 .
Prognostic factors — Poor prognostic factors in patients diagnosed with PE that should prompt vigilant monitoring 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 [CT]) – RV dysfunction due to PE, as assessed by echocardiography or CT, is associated with increased mortality [4,80-87]. However, compared with patients who are hemodynamically unstable, RV dysfunction in patients who are normotensive (ie, hemodynamically stable) does not consistently predict death, likely due to the poor definition and quantification of RV dysfunction on imaging. As examples:
•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 . 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.
•Several cohort studies and meta-analyses of hemodynamically stable patients reported that RV dysfunction was associated with an increase in mortality but the ability of RV dysfunction to independently predict death was variable [82-84].
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) .
Echocardiographic findings of RV dysfunction in patients with PE are discussed separately. (See "Clinical presentation, evaluation, and diagnosis of the 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 [81,89-98]. 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 [85,90,93,94,96,98-101].
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) [102,103]. The presence of right heart thrombus has been shown in several studies to be associated with RV dysfunction and high early mortality [102,104,105]. 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) .
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 .
Other — Additional predictors of poor prognosis that require further validation include the following:
●Hyponatremia (<130 mmol/L) and indicators of reduced renal dysfunction [106-108]
●Serum lactate (>2 mmoles/L) [109,110]
●White blood cell count (>12.6 x 109/L) 
●The Charlson co-morbidity index ≥1 
●Residual pulmonary vascular obstruction [113,114]
●Older age ≥65 years 
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 5) [116-119]. 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 5) : 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 . 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) . 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 . 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 .
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. 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 "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors".)
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 develop worsening oxygenation, respiratory failure, hypotension, pain, and/or fever. 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. Following definitive imaging, we suggest the approach below:
•Patients with recurrence should be investigated for the etiology of the recurrence and managed accordingly. (See 'Management of recurrence on therapy' below.)
•Patients without recurrence should be treated symptomatically with supplemental oxygen, analgesics, intravenous fluids, ventilation, vasopressors, and/or antibiotics, as indicated.
●Late complications of PE, including recurrence 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. (See "Clinical presentation, evaluation, and diagnosis of the adult with suspected acute pulmonary embolism".)
The development of persistent or progressive dyspnea, particularly during the first two years of diagnosis, should prompt the clinician to investigate for the development of CTEPH (affects up to 5 percent of patients). The clinical manifestations of CTEPH are discussed separately. (See "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 "Therapeutic use of unfractionated heparin and low molecular weight heparin" and "Therapeutic use of warfarin and other vitamin K antagonists" and "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors" and "Placement of vena cava filters and their complications", section on 'Complications' and "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Outcomes' and 'Embolectomy' above.)
●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 "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Making the decision to indefinitely anticoagulate'.)
●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 patients with established venous thromboembolism for acquired and inherited risk factors".)
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 "Mechanisms of nutrient absorption and malabsorption")
•Discontinuation for an anticipated procedure (see "Perioperative management of patients receiving anticoagulants")
•Altered dose requirement or pharmacokinetics for warfarin (eg, dietary vitamin K), target-specific oral anticoagulants (eg, drug interactions), or low molecular weight heparin (LMWH; 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, LMWH) are suspected. (See "Therapeutic use of unfractionated heparin and low molecular weight heparin", section on 'Heparin resistance/antithrombin deficiency' and "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors" 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 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 alternate agent, escalation of the dose of vitamin K antagonist or LMWH, and/or the addition of a vena cava filter, the details of which are discussed separately. (See "Treatment of venous thromboembolism in patients with malignancy", section on 'Management of recurrence' and "Treatment of the antiphospholipid syndrome", section on 'Treatment failure'.)
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 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 "Fat embolism syndrome".)
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 information: Pulmonary embolism (blood clot in the lungs) (The Basics)")
●Beyond the Basics topics (see "Patient information: Pulmonary embolism (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●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). 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. (See 'Initial approach and resuscitation' above and 'Initial therapies' above.)
●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):
•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 suggest 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. (Grade 2C).
•For patients with absolute contraindications to anticoagulant therapy or those with an unacceptably high risk of bleeding, we recommend that empiric anticoagulation not be administered (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.
•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.
●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). 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. (See 'Hemodynamically unstable' above.)
●For patients in whom definitive diagnostic testing excludes PE, anticoagulant therapy should be discontinued if it was initiated empirically, and alternative causes of the patient’s symptoms and signs should be sought. (See 'Definitive therapy' above.)
●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.)
•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). Outpatient anticoagulation is safe and effective in select patients at low risk of death (table 5), 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 "Anticoagulation in acute pulmonary embolism" and 'Anticoagulation' above.)
-For those who have contraindications to anticoagulation or have an unacceptably high bleeding risk, 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).
•For hemodynamically stable (ie, normotensive) patients with intermediate-risk/submassive PE, therapy should be individualized. 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, have high oxygen requirement, and/or severely tachycardic (table 4). (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Hemodynamically stable patients'.)
•For most patients with hemodynamically unstable PE, the following applies (see 'Hemodynamically unstable patients' above):
-For patients with refractory hypotension and without contraindications to thrombolysis (table 6), we suggest systemic thrombolytic therapy followed by anticoagulation rather than anticoagulation alone (Grade 2C). (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis" and 'Thrombolytic therapy' above.)
-For those in whom thrombolysis is contraindicated, 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.)
-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 "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Hemodynamically unstable patients'.)
●In patients with PE who are fully anticoagulated, we suggest early ambulation rather than bed rest, when feasible (Grade 2C). Other adjunctive therapies that are sometimes used in select patients who are fully anticoagulated include elastic graduated compression stockings and IVC filters. (See 'Adjunctive therapies' above.)
●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 5)) and/or biochemical markers that indicate right ventricle strain (natriuretic peptides, troponin) can predict early death and/or recurrence. (See 'Prognosis' above.)
●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.)
●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.)
- Carson JL, Kelley MA, Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med 1992; 326:1240.
- DONALDSON GA, WILLIAMS C, SCANNELL JG, SHAW RS. A reappraisal of the application of the Trendelenburg operation to massive fatal embolism. Report of a successful pulmonary-artery thrombectomy using a cardiopulmonary bypass. N Engl J Med 1963; 268:171.
- Tapson VF. Acute pulmonary embolism. N Engl J Med 2008; 358:1037.
- Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353:1386.
- Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e419S.
- Stein PD, Beemath A, Matta F, et al. Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med 2007; 120:871.
- Kabrhel C, Jaff MR, Channick RN, et al. A multidisciplinary pulmonary embolism response team. Chest 2013; 144:1738.
- Kucher N, Goldhaber SZ. Management of massive pulmonary embolism. Circulation 2005; 112:e28.
- Ghignone M, Girling L, Prewitt RM. Volume expansion versus norepinephrine in treatment of a low cardiac output complicating an acute increase in right ventricular afterload in dogs. Anesthesiology 1984; 60:132.
- Mathru M, Venus B, Smith RA, et al. Treatment of low cardiac output complicating acute pulmonary hypertension in normovolemic goats. Crit Care Med 1986; 14:120.
- Molloy WD, Lee KY, Girling L, et al. Treatment of shock in a canine model of pulmonary embolism. Am Rev Respir Dis 1984; 130:870.
- Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014; 35:3033.
- Boulain T, Lanotte R, Legras A, Perrotin D. Efficacy of epinephrine therapy in shock complicating pulmonary embolism. Chest 1993; 104:300.
- Jardin F, Genevray B, Brun-Ney D, Margairaz A. Dobutamine: a hemodynamic evaluation in pulmonary embolism shock. Crit Care Med 1985; 13:1009.
- Vasu MA, O'Keefe DD, Kapellakis GZ, et al. Myocardial oxygen consumption: effects of epinephrine, isoproterenol, dopamine, norepinephrine, and dobutamine. Am J Physiol 1978; 235:H237.
- Tanaka H, Tajimi K, Matsumoto A, Kobayashi K. Vasodilatory effects of milrinone on pulmonary vasculature in dogs with pulmonary hypertension due to pulmonary embolism: a comparison with those of dopamine and dobutamine. Clin Exp Pharmacol Physiol 1990; 17:681.
- Wolfe MW, Saad RM, Spence TH. Hemodynamic effects of amrinone in a canine model of massive pulmonary embolism. Chest 1992; 102:274.
- Baglin T. Fifty per cent of patients with pulmonary embolism can be treated as outpatients. J Thromb Haemost 2010; 8:2404.
- Kovacs MJ, Hawel JD, Rekman JF, Lazo-Langner A. Ambulatory management of pulmonary embolism: a pragmatic evaluation. J Thromb Haemost 2010; 8:2406.
- Erkens PM, Gandara E, Wells P, et al. Safety of outpatient treatment in acute pulmonary embolism. J Thromb Haemost 2010; 8:2412.
- Zondag W, Mos IC, Creemers-Schild D, et al. Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost 2011; 9:1500.
- Aujesky D, Roy PM, Verschuren F, et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet 2011; 378:41.
- Jiménez D, Aujesky D, Díaz G, et al. Prognostic significance of deep vein thrombosis in patients presenting with acute symptomatic pulmonary embolism. Am J Respir Crit Care Med 2010; 181:983.
- Zondag W, Kooiman J, Klok FA, et al. Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta-analysis. Eur Respir J 2013; 42:134.
- Zondag W, Hiddinga BI, Crobach MJ, et al. Hestia criteria can discriminate high- from low-risk patients with pulmonary embolism. Eur Respir J 2013; 41:588.
- Yoo HH, Queluz TH, El Dib R. Outpatient versus inpatient treatment for acute pulmonary embolism. Cochrane Database Syst Rev 2014; 11:CD010019.
- Goy J, Lee J, Levine O, et al. Sub-segmental pulmonary embolism in three academic teaching hospitals: a review of management and outcomes. J Thromb Haemost 2015; 13:214.
- Koning R, Cribier A, Gerber L, et al. A new treatment for severe pulmonary embolism: percutaneous rheolytic thrombectomy. Circulation 1997; 96:2498.
- Kuo WT, van den Bosch MA, Hofmann LV, et al. Catheter-directed embolectomy, fragmentation, and thrombolysis for the treatment of massive pulmonary embolism after failure of systemic thrombolysis. Chest 2008; 134:250.
- Chechi T, Vecchio S, Spaziani G, et al. Rheolytic thrombectomy in patients with massive and submassive acute pulmonary embolism. Catheter Cardiovasc Interv 2009; 73:506.
- Margheri M, Vittori G, Vecchio S, et al. Early and long-term clinical results of AngioJet rheolytic thrombectomy in patients with acute pulmonary embolism. Am J Cardiol 2008; 101:252.
- Nassiri N, Jain A, McPhee D, et al. Massive and submassive pulmonary embolism: experience with an algorithm for catheter-directed mechanical thrombectomy. Ann Vasc Surg 2012; 26:18.
- Ferrigno L, Bloch R, Threlkeld J, et al. Management of pulmonary embolism with rheolytic thrombectomy. Can Respir J 2011; 18:e52.
- Brady AJ, Crake T, Oakley CM. Percutaneous catheter fragmentation and distal dispersion of proximal pulmonary embolus. Lancet 1991; 338:1186.
- Schmitz-Rode T, Janssens U, Duda SH, et al. Massive pulmonary embolism: percutaneous emergency treatment by pigtail rotation catheter. J Am Coll Cardiol 2000; 36:375.
- Eid-Lidt G, Gaspar J, Sandoval J, et al. Combined clot fragmentation and aspiration in patients with acute pulmonary embolism. Chest 2008; 134:54.
- Müller-Hülsbeck S, Brossmann J, Jahnke T, et al. Mechanical thrombectomy of major and massive pulmonary embolism with use of the Amplatz thrombectomy device. Invest Radiol 2001; 36:317.
- Reekers JA, Baarslag HJ, Koolen MG, et al. Mechanical thrombectomy for early treatment of massive pulmonary embolism. Cardiovasc Intervent Radiol 2003; 26:246.
- Engelberger RP, Kucher N. Catheter-based reperfusion treatment of pulmonary embolism. Circulation 2011; 124:2139.
- Cuculi F, Kobza R, Bergner M, Erne P. Usefulness of aspiration of pulmonary emboli and prolonged local thrombolysis to treat pulmonary embolism. Am J Cardiol 2012; 110:1841.
- Heberlein WE, Meek ME, Saleh O, et al. New generation aspiration catheter: Feasibility in the treatment of pulmonary embolism. World J Radiol 2013; 5:430.
- Cardiopulmonary Bypass Vascular Catheter, Cannula, Or Tubing. Food and Drug Administration; Department of Health and Human Services, Silver Spring, MD 2014.
- Schmitz-Rode T, Günther RW, Pfeffer JG, et al. Acute massive pulmonary embolism: use of a rotatable pigtail catheter for diagnosis and fragmentation therapy. Radiology 1995; 197:157.
- Schmitz-Rode T, Janssens U, Schild HH, et al. Fragmentation of massive pulmonary embolism using a pigtail rotation catheter. Chest 1998; 114:1427.
- Kuo WT, Gould MK, Louie JD, et al. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol 2009; 20:1431.
- Nakazawa K, Tajima H, Murata S, et al. Catheter fragmentation of acute massive pulmonary thromboembolism: distal embolisation and pulmonary arterial pressure elevation. Br J Radiol 2008; 81:848.
- Kumar N, Janjigian Y, Schwartz DR. Paradoxical worsening of shock after the use of a percutaneous mechanical thrombectomy device in a postpartum patient with a massive pulmonary embolism. Chest 2007; 132:677.
- Aklog L, Williams CS, Byrne JG, Goldhaber SZ. Acute pulmonary embolectomy: a contemporary approach. Circulation 2002; 105:1416.
- Stein PD, Alnas M, Beemath A, Patel NR. Outcome of pulmonary embolectomy. Am J Cardiol 2007; 99:421.
- Osborne ZJ, Rossi P, Aucar J, et al. Surgical pulmonary embolectomy in a community hospital. Am J Surg 2014; 207:337.
- Bloomfield P, Boon NA, de Bono DP. Indications for pulmonary embolectomy. Lancet 1988; 2:329.
- Stein PD, Matta F. Pulmonary embolectomy in elderly patients. Am J Med 2014; 127:348.
- Meneveau N, Séronde MF, Blonde MC, et al. Management of unsuccessful thrombolysis in acute massive pulmonary embolism. Chest 2006; 129:1043.
- Leacche M, Unic D, Goldhaber SZ, et al. Modern surgical treatment of massive pulmonary embolism: results in 47 consecutive patients after rapid diagnosis and aggressive surgical approach. J Thorac Cardiovasc Surg 2005; 129:1018.
- Aymard T, Kadner A, Widmer A, et al. Massive pulmonary embolism: surgical embolectomy versus thrombolytic therapy--should surgical indications be revisited? Eur J Cardiothorac Surg 2013; 43:90.
- Fukuda I, Taniguchi S, Fukui K, et al. Improved outcome of surgical pulmonary embolectomy by aggressive intervention for critically ill patients. Ann Thorac Surg 2011; 91:728.
- Rosenberger P, Shernan SK, Mihaljevic T, Eltzschig HK. Transesophageal echocardiography for detecting extrapulmonary thrombi during pulmonary embolectomy. Ann Thorac Surg 2004; 78:862.
- Yalamanchili K, Fleisher AG, Lehrman SG, et al. Open pulmonary embolectomy for treatment of major pulmonary embolism. Ann Thorac Surg 2004; 77:819.
- Clarke DB, Abrams LD. Pulmonary embolectomy: a 25 year experience. J Thorac Cardiovasc Surg 1986; 92:442.
- Dauphine C, Omari B. Pulmonary embolectomy for acute massive pulmonary embolism. Ann Thorac Surg 2005; 79:1240.
- Clarke DB. Pulmonary embolectomy re-evaluated. Ann R Coll Surg Engl 1981; 63:18.
- Cadavid CA, Gil B, Restrepo A, et al. Pilot study evaluating the safety of a combined central venous catheter and inferior vena cava filter in critically ill patients at high risk of pulmonary embolism. J Vasc Interv Radiol 2013; 24:581.
- Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med 2003; 163:1711.
- Nijkeuter M, Söhne M, Tick LW, et al. The natural course of hemodynamically stable pulmonary embolism: Clinical outcome and risk factors in a large prospective cohort study. Chest 2007; 131:517.
- COON WW, WILLIS PW. Deep venous thrombosis and pulmonary embolism: prediction, prevention and treatment. Am J Cardiol 1959; 4:611.
- Soloff LA, Rodman T. Acute pulmonary embolism. II. Clinical. Am Heart J 1967; 74:829.
- Laporte S, Mismetti P, Décousus H, et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation 2008; 117:1711.
- Aujesky D, Obrosky DS, Stone RA, et al. A prediction rule to identify low-risk patients with pulmonary embolism. Arch Intern Med 2006; 166:169.
- den Exter PL, van Es J, Klok FA, et al. Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism. Blood 2013; 122:1144.
- Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis 1975; 17:259.
- Kyrle PA, Rosendaal FR, Eichinger S. Risk assessment for recurrent venous thrombosis. Lancet 2010; 376:2032.
- Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors for recurrence. Arterioscler Thromb Vasc Biol 2009; 29:298.
- Heit JA. Predicting the risk of venous thromboembolism recurrence. Am J Hematol 2012; 87 Suppl 1:S63.
- Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med 2010; 170:1710.
- Heit JA, Lahr BD, Petterson TM, et al. Heparin and warfarin anticoagulation intensity as predictors of recurrence after deep vein thrombosis or pulmonary embolism: a population-based cohort study. Blood 2011; 118:4992.
- Søgaard KK, Schmidt M, Pedersen L, et al. 30-year mortality after venous thromboembolism: a population-based cohort study. Circulation 2014; 130:829.
- Ng AC, Chung T, Yong AS, et al. Long-term cardiovascular and noncardiovascular mortality of 1023 patients with confirmed acute pulmonary embolism. Circ Cardiovasc Qual Outcomes 2011; 4:122.
- Hald EM, Enga KF, Løchen ML, et al. Venous thromboembolism increases the risk of atrial fibrillation: the Tromso study. J Am Heart Assoc 2014; 3:e000483.
- Klok FA, Zondag W, van Kralingen KW, et al. Patient outcomes after acute pulmonary embolism. A pooled survival analysis of different adverse events. Am J Respir Crit Care Med 2010; 181:501.
- ten Wolde M, Söhne M, Quak E, et al. Prognostic value of echocardiographically assessed right ventricular dysfunction in patients with pulmonary embolism. Arch Intern Med 2004; 164:1685.
- Becattini C, Casazza F, Forgione C, et al. Acute pulmonary embolism: external validation of an integrated risk stratification model. Chest 2013; 144:1539.
- Sanchez O, Trinquart L, Colombet I, et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur Heart J 2008; 29:1569.
- Trujillo-Santos J, den Exter PL, Gómez V, et al. Computed tomography-assessed right ventricular dysfunction and risk stratification of patients with acute non-massive pulmonary embolism: systematic review and meta-analysis. J Thromb Haemost 2013; 11:1823.
- Sanchez O, Trinquart L, Planquette B, et al. Echocardiography and pulmonary embolism severity index have independent prognostic roles in pulmonary embolism. Eur Respir J 2013; 42:681.
- Coutance G, Cauderlier E, Ehtisham J, et al. The prognostic value of markers of right ventricular dysfunction in pulmonary embolism: a meta-analysis. Crit Care 2011; 15:R103.
- Becattini C, Agnelli G, Germini F, Vedovati MC. Computed tomography to assess risk of death in acute pulmonary embolism: a meta-analysis. Eur Respir J 2014; 43:1678.
- Becattini C, Agnelli G, Vedovati MC, et al. Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test. Eur Heart J 2011; 32:1657.
- Grifoni S, Vanni S, Magazzini S, et al. Association of persistent right ventricular dysfunction at hospital discharge after acute pulmonary embolism with recurrent thromboembolic events. Arch Intern Med 2006; 166:2151.
- Cavallazzi R, Nair A, Vasu T, Marik PE. Natriuretic peptides in acute pulmonary embolism: a systematic review. Intensive Care Med 2008; 34:2147.
- Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med 2008; 178:425.
- Lega JC, Lacasse Y, Lakhal L, Provencher S. Natriuretic peptides and troponins in pulmonary embolism: a meta-analysis. Thorax 2009; 64:869.
- Lankeit M, Jiménez D, Kostrubiec M, et al. Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism. Eur Respir J 2014; 43:1669.
- Kucher N, Printzen G, Goldhaber SZ. Prognostic role of brain natriuretic peptide in acute pulmonary embolism. Circulation 2003; 107:2545.
- Kostrubiec M, Pruszczyk P, Bochowicz A, et al. Biomarker-based risk assessment model in acute pulmonary embolism. Eur Heart J 2005; 26:2166.
- Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation 2007; 116:427.
- Jiménez D, Uresandi F, Otero R, et al. Troponin-based risk stratification of patients with acute nonmassive pulmonary embolism: systematic review and metaanalysis. Chest 2009; 136:974.
- Janata KM, Leitner JM, Holzer-Richling N, et al. Troponin T predicts in-hospital and 1-year mortality in patients with pulmonary embolism. Eur Respir J 2009; 34:1357.
- Lankeit M, Jiménez D, Kostrubiec M, et al. Predictive value of the high-sensitivity troponin T assay and the simplified Pulmonary Embolism Severity Index in hemodynamically stable patients with acute pulmonary embolism: a prospective validation study. Circulation 2011; 124:2716.
- Vuilleumier N, Le Gal G, Verschuren F, et al. Cardiac biomarkers for risk stratification in non-massive pulmonary embolism: a multicenter prospective study. J Thromb Haemost 2009; 7:391.
- Lankeit M, Friesen D, Aschoff J, et al. Highly sensitive troponin T assay in normotensive patients with acute pulmonary embolism. Eur Heart J 2010; 31:1836.
- Hakemi EU, Alyousef T, Dang G, et al. The prognostic value of undetectable highly sensitive cardiac troponin I in patients with acute pulmonary embolism. Chest 2015; 147:685.
- Torbicki A, Galié N, Covezzoli A, et al. Right heart thrombi in pulmonary embolism: results from the International Cooperative Pulmonary Embolism Registry. J Am Coll Cardiol 2003; 41:2245.
- Casazza F, Bongarzoni A, Centonze F, Morpurgo M. Prevalence and prognostic significance of right-sided cardiac mobile thrombi in acute massive pulmonary embolism. Am J Cardiol 1997; 79:1433.
- Mollazadeh R, Ostovan MA, Abdi Ardekani AR. Right cardiac thrombus in transit among patients with pulmonary thromboemboli. Clin Cardiol 2009; 32:E27.
- Rose PS, Punjabi NM, Pearse DB. Treatment of right heart thromboemboli. Chest 2002; 121:806.
- Scherz N, Labarère J, Méan M, et al. Prognostic importance of hyponatremia in patients with acute pulmonary embolism. Am J Respir Crit Care Med 2010; 182:1178.
- Kostrubiec M, Łabyk A, Pedowska-Włoszek J, et al. Assessment of renal dysfunction improves troponin-based short-term prognosis in patients with acute symptomatic pulmonary embolism. J Thromb Haemost 2010; 8:651.
- Kostrubiec M, Łabyk A, Pedowska-Włoszek J, et al. Neutrophil gelatinase-associated lipocalin, cystatin C and eGFR indicate acute kidney injury and predict prognosis of patients with acute pulmonary embolism. Heart 2012; 98:1221.
- Vanni S, Viviani G, Baioni M, et al. Prognostic value of plasma lactate levels among patients with acute pulmonary embolism: the thrombo-embolism lactate outcome study. Ann Emerg Med 2013; 61:330.
- Vanni S, Jiménez D, Nazerian P, et al. Short-term clinical outcome of normotensive patients with acute PE and high plasma lactate. Thorax 2015; 70:333.
- Venetz C, Labarère J, Jiménez D, Aujesky D. White blood cell count and mortality in patients with acute pulmonary embolism. Am J Hematol 2013; 88:677.
- Ng AC, Chow V, Yong AS, et al. Prognostic impact of the Charlson comorbidity index on mortality following acute pulmonary embolism. Respiration 2013; 85:408.
- Meneveau N, Ider O, Seronde MF, et al. Long-term prognostic value of residual pulmonary vascular obstruction at discharge in patients with intermediate- to high-risk pulmonary embolism. Eur Heart J 2013; 34:693.
- Poli D, Cenci C, Antonucci E, et al. Risk of recurrence in patients with pulmonary embolism: predictive role of D-dimer and of residual perfusion defects on lung scintigraphy. Thromb Haemost 2013; 109:181.
- Cefalo P, Weinberg I, Hawkins BM, et al. A comparison of patients diagnosed with pulmonary embolism who are ≥65 years with patients <65 years. Am J Cardiol 2015; 115:681.
- Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005; 172:1041.
- Wicki J, Perrier A, Perneger TV, et al. Predicting adverse outcome in patients with acute pulmonary embolism: a risk score. Thromb Haemost 2000; 84:548.
- Uresandi F, Otero R, Cayuela A, et al. [A clinical prediction rule for identifying short-term risk of adverse events in patients with pulmonary thromboembolism]. Arch Bronconeumol 2007; 43:617.
- Jiménez D, Kopecna D, Tapson V, et al. Derivation and validation of multimarker prognostication for normotensive patients with acute symptomatic pulmonary embolism. Am J Respir Crit Care Med 2014; 189:718.
- Jiménez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170:1383.
- Kohn CG, Mearns ES, Parker MW, et al. Prognostic accuracy of clinical prediction rules for early post-pulmonary embolism all-cause mortality: a bivariate meta-analysis. Chest 2015; 147:1043.