Acute pulmonary embolism in adults: Thrombolytic therapy in intermediate- and high-risk patients

INTRODUCTION — 

Thrombolytic therapy is used in patients with acute pulmonary embolism (PE) to rapidly dissolve thrombus and improve cardiorespiratory hemodynamics. While anticoagulant therapy is sufficient in most patients, a select proportion may benefit from thrombolytic therapy. However, it is associated with bleeding, which can be catastrophic. Thus, careful patient selection is critical to the success of this therapy.

The approach to patient selection for thrombolytic therapy in acute PE is discussed here. Thrombolysis for deep vein thrombosis of the upper and lower extremities is discussed elsewhere. (See "Catheter-directed thrombolytic therapy in deep venous thrombosis of the lower extremity: Patient selection and administration" and "Primary (spontaneous) upper extremity deep vein thrombosis", section on 'Thrombolytic therapy'.)

MAKING THE DECISION

Should the diagnosis be confirmed? — Because the adverse effects of thrombolytic therapy-related bleeding can be devastating, we prefer that the diagnosis of acute PE be confirmed on radiographic imaging. This is typically done using computed tomographic (CT) pulmonary angiography (CTPA). Also acceptable are ventilation/perfusion scanning, portable perfusion scanning, pulmonary arteriography (which often immediately precedes catheter-directed therapy [CDT]), or echocardiography (when thrombus-in-transit is seen (see 'Clot-in-transit' below)) [1]. Exceptions include the following:

●During emergencies, when PE is highly suspected but not diagnosed and obtaining imaging is unsafe or not available, thrombolytic therapy may be administered if a presumptive diagnosis is made with bedside transthoracic echocardiography (TTE) or transesophageal echocardiography that shows right ventricular (RV) enlargement/hypokinesis and/or regional wall motion abnormalities that spare the RV apex (McConnell sign). Lower extremity thrombus seen on bedside ultrasonography is not diagnostic but may be sufficient to support the administration of thrombolytic agents in urgent or life-threatening situations.

●Rarely, thrombolytic therapy may be administered in the absence of imaging using an empiric clinical diagnosis during cardiopulmonary resuscitation. (See 'Efficacy' below and 'Cardiopulmonary resuscitation' below.)

The diagnosis of PE is discussed in detail separately. (See "Clinical presentation and diagnostic evaluation of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Hemodynamically unstable patients (high-risk PE)' and "Clinical presentation and diagnostic evaluation of the nonpregnant adult with suspected acute pulmonary embolism", section on 'CTPA'.)

Factors that influence the decision — Experts should evaluate the risk of death from PE (table 1) and the risk of bleeding from the thrombolytic agent (table 2). (See 'Assessing risk of death from pulmonary embolism' below and 'Assessing risk of bleeding' below.)

We believe that the importance placed on the risk of bleeding is relative to the strength of the indication (table 3) (ie, the risk of death from PE). As examples:

●The risk of bleeding from surgical trauma has greater weight if the indication for systemic thrombolytic therapy is, for example, mild RV hypokinesis with normal biomarkers (intermediate-risk PE), than if the indication is shock or cardiac arrest (high-risk PE).

●While a patient with PE-induced shock who is unconscious and requiring very high doses of vasopressors (high-risk PE) is likely to benefit from immediate intravenous systemic thrombolytic therapy, the indication is not as apparent in a patient who has low blood pressure for 20 minutes but is awake, alert, and comfortable with low oxygenation requirement.

The complexity of this decision underscores the importance of expert consultation. (See 'Pulmonary embolism response team' below.)

Once the decision is made to proceed with thrombolysis, the clinician needs to decide the optimal mode and timing of administration. While this evaluation is ongoing, patients should be anticoagulated with intravenous unfractionated heparin or low molecular weight heparin, provided the bleeding risk is not high. (See "Venous thromboembolism: Initiation of anticoagulation", section on 'Selection of agent'.)

Assessing risk of death from pulmonary embolism — We assess each patient for the risk of death due to PE as the following (table 4):

●Low – Low-risk patients are normotensive with normal RV imaging (CTPA or TTE) and normal biomarkers (troponin or brain natriuretic peptide [BNP]). We do not evaluate these patients for thrombolytic therapy since there is no proven benefit compared with therapeutic anticoagulation. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Low-risk PE'.)

●Intermediate (submassive) – Intermediate-risk patients are normotensive with either RV dysfunction (CTPA or TTE) and/or elevated biomarkers (troponin or BNP). We monitor these patients for clinical decompensation and evaluate for thrombolytic therapy, although only a select few on the severe end of the spectrum receive it. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Intermediate-risk PE'.)

●High (massive) – High-risk patients are hemodynamically unstable. We evaluate these patients for advanced reperfusion therapies since the benefit often outweighs the risk. This includes thrombolysis, CDT (catheter-directed thrombolysis or suction thrombectomy), or surgical thrombectomy. What qualifies as "unstable" is discussed separately. (See 'Hemodynamically unstable (high-risk pulmonary embolism)' below and "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'High-risk PE (unstable)'.)

Assessing risk of bleeding — Absolute and relative contraindications to systemic thrombolytic therapy in acute PE are listed in the table (table 2) [2].

Thrombolytic therapy may cause moderate bleeding in menstruating females, but it has rarely been associated with major hemorrhage. (See 'Monitoring and management of bleeding' below.)

Agents such as aspirin or dual antiplatelet therapy increase the risk of bleeding, but are not contraindications to thrombolytic therapy.

Close monitoring is advised in patients who have had PE-induced syncope with resultant head trauma, even if brain CT shows no associated abnormality; in such cases, the risk of bleeding may be increased due to the trauma that may be undetected by head CT. In some cases, selecting a mode of delivery, such as catheter-directed thrombolysis, may be warranted.

Pulmonary embolism response team — When deciding whether, when (immediate or delayed), and how (systemic, catheter-directed, with or without mechanical clot lysis) to administer thrombolytic therapy, most experts advise early involvement of expert consultants. Many institutions have multidisciplinary PE response teams (PERTs) for this purpose.

Further details on the value of PERTs are provided separately. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Pulmonary embolism response teams'.)

INITIAL RESUSCITATION — 

Initial resuscitation of patients with PE is depicted in the table (table 5) and discussed in detail separately. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Supportive therapies'.)

HEMODYNAMICALLY UNSTABLE (HIGH-RISK PULMONARY EMBOLISM) — 

Patients with high-risk PE are those with hypotension, shock, or cardiac arrest due to PE. Clinically significant hypotension is defined as systolic blood pressure (BP) <90 mmHg or hypotension that requires vasopressors or inotropic support despite adequate filling status in combination with end-organ hypoperfusion; persistent hypotension or a drop in systolic BP of ≥40 mmHg from baseline for a period >15 minutes; and hypotension not explained by other causes, such as hypovolemia, sepsis, arrhythmia, or left ventricular dysfunction from acute myocardial ischemia or infarction (table 4) [2,3]. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Assess mortality risk (low, intermediate, high)'.)

High-risk PE and low bleeding risk: Systemic full-dose thrombolysis — For patients with a low bleeding risk, acute high-risk PE (first or recurrent event) is the only widely accepted indication for full-dose intravenous systemic thrombolysis, typically tissue-type plasminogen activator (tPA) (table 3). Evidence from randomized and observational studies indicates that systemic thrombolytic therapy leads to early and rapid hemodynamic improvement (eg, improved pulmonary arterial BP, right ventricular [RV] function, and pulmonary perfusion) and is associated with a mortality benefit. Most experts believe that these benefits are sufficient to justify thrombolytic therapy despite the increased risk of major or catastrophic bleeding. These data are discussed below. (See 'Efficacy' below.)

Catheter-directed therapies (CDTs) with or without thrombolysis may be an option in patients who are on the "more stable" end of the hemodynamically unstable spectrum (eg, low-dose stable vasopressor) [2,3]. (See 'Catheter-directed thrombolysis' below and 'Catheter-directed therapies (CDTs)' below.)

Administration — When the indication is clear and the risk of bleeding is low, thrombolytic therapy should be administered immediately. Necessary invasive procedures (eg, intravenous access) should be quickly performed while the infusion is being prepared and all other invasive procedures delayed until after the infusion is complete. Central intravenous access is not required.

Anticoagulation before thrombolysis — The preferred anticoagulant is typically unfractionated heparin (UFH), although the use of low molecular weight (LMW) heparin is not a contraindication to thrombolysis.

We discontinue the anticoagulant therapy immediately before and during the thrombolytic infusion to minimize the risk of bleeding, although some clinicians may continue anticoagulation during the infusion.

Regardless of the practice, the potential risk of bleeding (when anticoagulation is continued) and the potential risk of recurrent embolism (when anticoagulation is discontinued) are unknown.

Agent selection and dosing — Full-dose intravenous thrombolytic infusion regimens are the most common method of administering these agents. Only limited data support reduced-dose regimens in this population. (See 'Efficacy' below.)

●Agent – Recombinant tPA is the most common agent used (eg, alteplase or tenecteplase). Streptokinase (SK) and recombinant human urokinase (UK) are no longer available for this indication in the United States. Other related formulations of tPA, including lanoteplase and reteplase, have not been studied in the treatment of acute PE.

The biologic characteristics of thrombolytic agents and their role in acute myocardial infarction and stroke are discussed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Acute ST-elevation myocardial infarction: Management of fibrinolysis".)

●Dose – Dosing regimens for alteplase and tenecteplase are as follows:

•Alteplase – The US Food and Drug Administration-approved dosing regimen for intravenous alteplase is 100 mg administered over two hours. In more urgent situations, it is appropriate to administer tPA as a bolus, as an infusion over 15 minutes, or as a 50 mg intravenous bolus followed by an infusion of 50 mg over the next two hours [2,4,5]. However, none of these regimens has been directly compared with a two-hour infusion of tPA.

Evidence from small randomized trials suggests that shorter infusions (ie, ≤2 hours for tPA) achieve more rapid clot lysis and are associated with lower rates of bleeding than longer infusions (ie, ≥12 and ≥24 hours for UK and SK, respectively) [2,4].

A bolus infusion of thrombolytic therapy (eg, 50 mg tPA) is appropriate for patients with PE-related cardiac arrest [2]. (See 'Cardiopulmonary resuscitation' below.)

•Tenecteplase – Tenecteplase is rarely used in the United States. However, it was administered as a weight-based bolus infusion for hemodynamically stable patients with RV dysfunction due to PE (the PEITHO trial; 30 mg for ≤60 kg, 35 mg for 61 to 69 kg, 40 mg for 70 to 79 kg, 45 mg for 80 to 89, 50 mg for ≥90 kg). The details of this trial are provided below. (See 'Systemic full-dose thrombolytic therapy' below.)

Monitoring and management of bleeding — During the infusion, the patient should be monitored closely for stability or improvement of vital signs and oxygenation, development of neurologic deficits, and hemodynamic or obvious signs of bleeding. Generally, clinical improvement is noted within the first hour of the infusion. When infusion of the thrombolytic agent is complete, intravenous UFH is restarted, as discussed below. (See 'Anticoagulation following thrombolysis' below.)

Considerable clinical judgment is needed when patients have bleeding while on thrombolytic therapy.

●Minor bleeding – Minor bleeding during thrombolytic therapy is common and is not generally an indication to stop therapy. However, the definition of minor bleeding is unclear. In our opinion, minor bleeding is that which occurs at sites of invasive procedures, such as venipuncture or arterial puncture sites, or in the skin and gums [6,7]. Bleeding from vascular puncture sites should be controlled with manual compression followed by a pressure dressing. Many experts also tolerate bleeding from menstruation and bleeding that can be controlled at compressible sites (eg, epistaxis or wounds). Minor bleeding from the gastrointestinal or genitourinary tract may also be managed by following clinically (eg, vital signs and hemoglobin).

●Major bleeding – We immediately stop the infusion and treat the bleeding when signs of major bleeding are present (eg, hemodynamic compromise, mental status changes, significant reductions in hemoglobin [eg, by 1 to 2 g/dL], need for transfusion, and copious amounts of bleeding).

If intracranial bleeding is suspected clinically following stabilization, a non-contrast-enhanced CT scan of the brain and emergent neurologic/neurosurgical consultation should also be obtained. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".)

There is a paucity of data regarding indications for reversal of thrombolytics. If patients continue to have significant or refractory bleeding despite cessation of the thrombolytic agent, we typically transfuse patients with 10 units of cryoprecipitate (with or without two units of fresh frozen plasma) and then reassess. In addition, we hold anticoagulant therapy and consider reversal with protamine sulfate and an inferior vena cava (IVC) filter to prevent further PE.

When considering reversal, the relative severity of the bleeding and the thromboembolic process must be weighed in view of the potential to exacerbate thrombosis. This approach is based on our experience and that of other intensivists for the management of thrombolytic-related intracranial hemorrhage (ICH) in patients with stroke [8].

Further details regarding reversal of thrombolytic agents and heparin are provided separately. The dose and administration of protamine sulfate are also discussed in detail elsewhere. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Bleeding' and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Management of symptomatic intracerebral hemorrhage' and "Reversal of anticoagulation in intracranial hemorrhage".)

Anticoagulation following thrombolysis

●Agent selection – Following thrombolysis, patients should be fully anticoagulated with intravenous UFH. If patients have received LMW heparin, we do not start UFH until the next dose of LMW heparin would have been due. We generally avoid initiating longer-acting anticoagulants (eg, LMW heparin) and oral agents (eg, direct oral anticoagulants [DOACs], warfarin) for at least 24 hours to ensure that there is no delayed bleeding that would require immediate cessation of anticoagulation.

●Dosing – While some experts start a heparin infusion without a bolus, most experts check an activated partial thromboplastin time (aPTT) and resume UFH without a loading dose when the aPTT is less than twice its upper limit of normal. If the aPTT exceeds this value, we repeat it every four hours until it is less than twice its upper limit of normal, at which time, we resume a heparin infusion. The protocol used to administer UFH is the same as that administered to patients with acute PE. (See "Venous thromboembolism: Initiation of anticoagulation".)

Once stable for 24 to 48 hours, patients should be transitioned to an oral agent (eg, DOAC or warfarin). The duration of long-term anticoagulation following thrombolysis is generally the same as for patients who have not received a thrombolytic agent. (See "Venous thromboembolism: Anticoagulation after initial management".)

Short-term follow-up (24 to 48 hours) — Patients should be monitored for continued signs of improvement (eg, reduced heart rate and respiratory rate and improved oxygenation and BP) following the infusion. Generally, clinical improvement may continue for a few hours and days beyond completion of the infusion.

Although not routine, many experts also perform echocardiography 24 hours after the infusion to examine the size and function of the RV. While many cases demonstrate improved RV size and function, complete RV recovery may lag behind clinical improvement. (See "Echocardiographic assessment of the right heart".)

It is not routine to obtain repeat imaging for PE unless symptoms remain or worsen.

Routine or specialized venous thromboembolism clinic follow-up while the patient is receiving long-term anticoagulation is described separately. (See "Echocardiographic assessment of the right heart" and "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Monitoring and follow-up' and "Venous thromboembolism: Anticoagulation after initial management", section on 'Monitoring'.)

Efficacy — A consistent finding among studies is that thrombolytic therapy leads to early hemodynamic improvement and a mortality benefit exists but at the cost of increased major bleeding [9-16]. For high-risk patients, who are at increased risk of mortality and similar risk of major bleeding compared with the rest of the population, these data suggest substantial benefit. Some limitations include small-size trials; patient crossover between the groups; variable and mixed populations (eg, unstable, stable); changing definitions of high-risk PE over time; and variable thrombolytic agents, methods of administration, and dosing. Despite the likely benefit, real-world data suggest that systemic thrombolytic therapy is not administered as frequently as it should be [17].

●Mortality – Thrombolytic therapy has been shown in several meta-analyses to improve mortality at the expense of increased rates of bleeding in patients with intermediate- or high-risk PE [3,14-16]. As examples:

•In a 2021 meta-analysis of 29 studies of patients with acute PE (high- and intermediate-risk PE), compared with heparin alone, thrombolysis resulted in a reduction in mortality (odds ratio [OR] 0.57, 95% CI 0.37-0.87; 2.8 versus 4.9 percent; 30 to 6 fewer deaths) but at the expense of major bleeding (OR 2.9, 95% CI 1.95-4.31; 10.4 versus 3.8 percent; 33 to 107 more events) [3].

•In another 2021 meta-analysis of 21 trials that included patients with both high- and intermediate-risk PE, the administration of thrombolytic agents followed by heparin reduced the odds of death compared with heparin alone (OR 0.58, 95% CI 0.38-0.88) [18]. The risk of major bleeding was increased in those who received thrombolytic therapy (OR 2.84, 95% CI 1.92-4.2) as was the risk of hemorrhagic stroke (OR 7.59, 95% CI 1.38-41.72).

Subgroup analysis of an older meta-analysis reported that the mortality benefit was not significant in patients older than 65 years (2.1 versus 3.6 percent; OR 0.55, 95% CI 0.29-1.05).

Mortality in the high-risk group alone has not been well-studied, but the higher baseline risk of death almost certainly translates into increased benefit.

●Pulmonary hemodynamics – Thrombolytic therapy improves pulmonary arterial BP, RV function, and pulmonary perfusion more quickly than heparin alone [19-24]. Improvement generally occurs over the first several hours and days. However, it is uncertain whether these beneficial effects persist long-term since data suggest that thrombolytic therapy does not prevent the development of chronic thromboembolic pulmonary hypertension [25].

In a prospective trial of 40 consecutive patients with high-risk acute PE, patients who received thrombolytic therapy had improved RV function 12 hours after the initiation of therapy compared with patients who received anticoagulation alone [19]. However, one week later, there was no difference in RV function. This suggests RV function improved later in patients who did not receive thrombolytic therapy.

●Recurrent thromboembolism – Several meta-analyses report reduced rates of recurrent thromboembolism with thrombolytic therapy compared with anticoagulation alone (OR ranging from 0.4 to 0.54) [3,16,18].

The efficacy of reduced-dose systemic thrombolytic therapy has been inadequately studied in high-risk PE. However, one study, in which one-third of patients were hemodynamically unstable due to acute PE, reported a possible mortality benefit from reduced-dose tPA. Further details of this study and of other studies that examined the efficacy of reduced-dose tPA in patients with stable PE are provided below. (See 'Reduced-dose systemic thrombolytic therapy' below.)

Bleeding rates — Rates of major bleeding among systemic agents range from 10 to 20 percent [6,16,26-29]. One meta-analysis of 16 trials compared bleeding rates among thrombolytic agents (mostly systemic agents) with those associated with anticoagulant therapy (usually heparin) [16]. The use of thrombolytic agents was associated with greater overall rates of major bleeding (9.2 versus 3.4 percent; OR 2.73, 95% CI 1.91-3.91) as well as higher rates of ICH (1.5 versus 0.2 percent; OR 4.63, 95% CI 1.78-12.04). Bleeding was three times greater in those >65 years compared with those who were ≤65 years (12.9 versus 4.1 percent; OR 3.1, 95% CI 2.1-4.56), which may explain a lack of mortality benefit in this age group [16].

The most potentially devastating complication associated with systemic thrombolytic therapy is ICH [30]. Clinical trials suggest that rates of ICH can be as high as 13 percent but are on average 2 to 5 percent [6,16,26-28]. Rates of ICH are higher in patients >65 years of age (12.9 versus 4.1 percent in one meta-analysis) [16]. (See 'High-risk PE and low bleeding risk: Systemic full-dose thrombolysis' above.)

Few studies have examined the bleeding source. In a retrospective analysis of 104 patients with acute PE who received intravenous tPA (alteplase), the principal site of bleeding was unknown in 45 percent, gastrointestinal in 30 percent, retroperitoneal in 15 percent, intracranial in 5 percent, and splenic in 5 percent [29]. Independent predictors of major hemorrhage were administration of catecholamines for systemic arterial hypotension (OR 115, 95% CI 9.4-1411), malignancy (OR 16, 95% CI 3.2-80), diabetes mellitus (OR 9.6, 95% CI 1.7-54), and elevated international normalized ratio (OR 6, 95% CI 1.5-22).

Patients who fail systemic thrombolysis — Catheter-based therapies are options for patients in whom systemic thrombolysis fails to reverse shock, provided that the necessary local expertise is available [3,31,32]. Occasionally, some clinicians repeat systemic thrombolysis (full- or half-dose). Choosing among these is dependent upon available resources and bleeding risk.

Data in this population are limited. 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) [32]. In addition, there were fewer deaths and fewer major bleeding complications associated with surgical embolectomy, which did not achieve statistical significance. However, catheter-based therapies were not available at the time of this publication.

High-risk PE and high bleeding risk: Catheter-directed therapies — Catheter-directed techniques are preferred in this population when available.

Catheter-directed therapies (CDTs) — In patients with high-risk PE who are also at high risk of fatal bleeding or have other contraindications to systemic thrombolytic therapy (table 2), we suggest CDTs (eg, suction, low-dose thrombolytic agent) [2,3]. Surgical embolectomy is an alternative if catheter-directed expertise is not available (see 'Alternatives' below). If neither of these therapies is feasible, anticoagulation or placement of an IVC filter are options. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Definitive therapy'.)

Evidence to support this approach is derived from our experience and limited indirect data in patients with intermediate- or high-risk PE who are at low risk of bleeding as well as the presumptive lower procedural risk associated with CDTs when compared with surgical embolectomy. These therapies are discussed in the sections below. (See 'Suction embolectomy' below and 'Catheter-directed thrombolysis' below.)

Choosing a CDT method — CDTs include therapies focused on mechanical thrombus removal (eg, suction embolectomy) and catheter-directed thrombolysis (with or without ultrasound).

Choosing among these catheter-directed techniques is individualized and expertise-dependent. For example, suction embolectomy may be preferred when the bleeding risk is high and thrombolysis is contraindicated (table 2). In contrast, experts without suction embolectomy expertise may administer a small dose of thrombolytic agent via a catheter to maximize thrombus removal while minimizing the bleeding risk (eg, life-threatening PE in patients with a minor fracture or compressible surgical wound); dosing is clinician-dependent.

Since CDTs are not universally available and the decision complex, transfer to a center of expertise should be considered after initial stabilization [33]. The method of administration and complications are discussed below. (See 'Catheter-directed thrombolysis' below.)

Suction embolectomy — Thrombus can be manually aspirated through a large-lumen catheter using an aspiration syringe and a hemostatic valve [34,35].

●One retrospective study suggested improved in-hospital mortality and decreased intensive care unit length of stay for patients with acute central PE with a flow retrieval suction device [36].

●In another prospective study of 53 patients with high-risk PE (FLAME), use of a flow retrieval suction device was associated with lower hospital mortality compared with other therapies (2 versus 30 percent) [37].

More advanced catheters have been used to remove soft fresh thrombi or during extracorporeal bypass. This applies most readily to large thromboemboli in the IVC or right heart chambers (see 'Clot-in-transit' below). Such devices cannot easily access the pulmonary arteries to suction more distal emboli [38].

Catheter-directed thrombolysis — Catheter-directed thrombolysis has the potential advantage of administering lower doses of thrombolytic agent, thereby reducing the risk of bleeding compared with systemic therapy.

Catheter-directed thrombolysis is more commonly performed in patients with intermediate-risk PE at low risk of bleeding (see 'Catheter-directed thrombolysis' below). Data describing the efficacy of catheter-directed thrombolysis in high-risk PE are limited by small sample size, inadequate power to estimate survival benefit, use of surrogate outcome measures, and lack of data on meaningful outcomes over a longer period (weeks to months). Further randomized studies clarifying the population that might benefit from this approach are needed before catheter-directed thrombolysis can be routinely used for patients with high-risk acute PE. As examples [39-43]:

●A 2019 meta-analysis of 28 mostly observational studies totaling 2135 patients, 47 percent of whom had high-risk PE, reported significant improvement in cardiopulmonary hemodynamics with ultrasound-assisted catheter-directed thrombolysis compared with baseline [41]. In-hospital mortality was 3 percent and total long-term mortality was 4 percent.

●A single-arm prospective trial of 150 patients, 20 percent of whom were considered to have high-risk PE (SEATTLE II), reported that at 48 hours, catheter-directed thrombolysis resulted in a significant reduction in pulmonary artery pressure without any episodes of major bleeding [42]. No ICHs were reported.

●In a database analysis of nearly 15,000 patients with high-risk PE, CDTs (thrombolysis and/or mechanical embolectomy) were associated with a lower risk of 90-day all-cause mortality (hazard ratio [HR] 0.77, 95% CI 0.71-0.83) and venous thromboembolism recurrence (HR 0.46, 95% CI 0.34-0.63) [43].

Others — Other techniques, such as rheolytic embolectomy (pressurized saline-injected and macerated thrombus is aspirated) [44-49] and rotational embolectomy (a rotating device at the catheter tip fragments thrombus that can be aspirated), [50-54] have largely fallen out of favor.

Alternatives

Surgical embolectomy — The surgical removal of thrombi is typically only performed in large medical centers because an experienced surgeon is required. In high-risk patients, we advise early consultation with surgical expertise [55].

Historically, surgical embolectomy has a high mortality, particularly in older patients (2 to 46 percent) [32,56-67] and following cardiac arrest [56,68-71]. However, newer data suggest mortality may be on the lower end of this range [55]. In one study of 36 patients with shock due to acute PE, the operative mortality associated with surgical embolectomy was 3 percent [69]. In contrast, among patients with acute PE who were resuscitated from a cardiac arrest and then underwent surgical embolectomy, operative mortality was 75 percent [69,70].

Surgery involves a thoracotomy and cardiopulmonary bypass. Only proximal emboli are amenable to surgical removal (ie, right ventricle, main pulmonary artery, and extrapulmonary branches of the pulmonary artery) whereas distal thrombus is generally not amenable (eg, intrapulmonary branches of the PA).

Transesophageal echocardiography (TEE) should be performed before or during embolectomy to look for extrapulmonary thrombi (eg, in the right atrium, RV, 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) [72].

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" and "Postoperative airway and pulmonary complications in adults: Management following initial stabilization".)

Limited data describe outcomes with surgical embolectomy.

●In a retrospective database study, similar 30-day mortality was reported in the 257 patients with PE who underwent surgical embolectomy compared with 1854 patients who underwent thrombolysis (15 versus 13 percent) [73].

●In a series of 115 patients who underwent surgical embolectomy, those with high-risk PE had higher operative mortality compared with patients who had intermediate-risk PE (10 versus 4 percent) and worse survival (75 versus 93 percent) [64].

●Another retrospective series of patients who underwent embolectomy reported an in-hospital mortality of only 2 percent and immediate improvement of RV pressures that persisted at 30 months [59].

Other options — In the absence of contraindications, reduced-dose systemic thrombolysis may be an option in patients with high-risk PE who are also at high risk of bleeding, although data only exist in patients with intermediate-risk PE at low risk of bleeding. (See 'Reduced-dose systemic thrombolytic therapy' below.)

Venoarterial (V-A) extracorporeal membrane oxygenation (ECMO) may also be an option for hemodynamic support or bridge to surgery. V-A ECMO can also be used to stabilize patients while CDTs are undertaken. (See "Extracorporeal life support in adults: Management of venoarterial extracorporeal membrane oxygenation (V-A ECMO)", section on 'Acute decompensated pulmonary vascular disease' and "Extracorporeal life support in adults: Management of venoarterial extracorporeal membrane oxygenation (V-A ECMO)", section on 'Sudden cardiac arrest (extracorporeal cardiopulmonary resuscitation)'.)

HEMODYNAMICALLY STABLE WITH INTERMEDIATE-RISK PULMONARY EMBOLISM — 

This group is defined as having both imaging and/or biochemical evidence of right ventricular (RV) dysfunction (table 4) (see "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Assess mortality risk (low, intermediate, high)'). While most patients with intermediate-risk PE are anticoagulated (as the sole therapy), a select few may benefit from thrombolysis. Importantly, patients in this group should be evaluated by experts in thrombolysis and closely monitored for deterioration so that anticoagulant therapy can be promptly switched to thrombolytic therapy. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Intermediate-risk PE'.)

Rationale for reperfusion and patient selection

Rationale — The rationale for thrombolysis in this population is based on the observation that severe RV dysfunction is associated with a worse prognosis than mild or no RV dysfunction [74]. However, the definition of severe RV dysfunction is unclear and randomized trials have not shown a convincing or consistent mortality benefit from thrombolytic therapy in this population. Nonetheless, it is likely that patients on the higher end of the spectrum benefit such that correct patient selection is critical to the success of thrombolytic therapy in this group. (See 'Efficacy' below.)

Patient selection — We believe that careful assessment by knowledgeable experts is the cornerstone of appropriate patient selection in this contentious group (see 'Pulmonary embolism response team' above). Our approach is as follows:

●For most patients with intermediate-risk acute PE, reperfusion therapy is not warranted, and patients should be immediately anticoagulated and monitored closely. Further details are provided separately (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Intermediate-risk PE'.)

●In patients with intermediate-risk PE who are assessed to be at the highest risk of death from PE, reperfusion therapy can be considered on a case-by-case basis [2,3]. Data to support this practice are discussed separately. (See 'Efficacy' below.)

As a guide, patients most likely to benefit include the following (table 1):

•Patients with intermediate-high-risk PE – Patients with intermediate-high-risk PE (as opposed to intermediate-low-risk PE) have both imaging and biochemical evidence of RV dysfunction (table 4). These patients may be candidates especially when they have worsening hypotension (not meeting high-risk criteria), severe or worsening respiratory distress or hypoxemia, worsening or persistent tachycardia >120 beats per minute, right-sided thrombus in transit, syncope, or elevated lactate. Some experts also consider reperfusion therapy when patients have limited cardiopulmonary reserve.

The clinician needs to distinguish acute from chronic dysfunction since thrombolysis is not appropriate in the latter. As examples:

-Findings of pulmonary hypertension or an old echocardiography showing RV dysfunction suggest a component of chronic RV dysfunction.

-We use clot burden as a guide to determine whether our clinical findings of RV failure can be explained by PE. Approximately 25 to 30 percent of the pulmonary vasculature must be occluded before the pulmonary artery pressure and RV afterload increases [75]. A low thrombus burden should prompt an evaluation for chronic RV failure due to other causes. A high clot burden with RV failure may support acute RV failure due to PE.

High thrombus burden is poorly defined and robust data to support increased mortality from PE with this feature is lacking. The MOPETT trial defined large thrombus burden as >70 percent involvement of the pulmonary vascular bed with embolism in two or more lobar arteries or main pulmonary arteries on CT pulmonary angiography or by a high probability ventilation/perfusion (V/Q) scan showing V/Q mismatch in two or more lobes [23]. However, reduced-dose systemic thrombolysis in this population did not result in a mortality benefit; further details of this study are provided below. (See 'Reduced-dose systemic thrombolytic therapy' below.)

•Patients who deteriorate due to PE while therapeutic on anticoagulant therapy – This includes patients with low- or intermediate-risk PE with worsening gas exchange, falling blood pressure without meeting the shock or hypotension definition criteria, and/or a rising heart rate. While no data support this practice, it is supported by expert consensus [1,3].

The evaluation of normotensive cardiogenic shock is a new concept. In a retrospective cohort, 40 percent of patients with intermediate-risk PE had a depressed cardiac index consistent with normotensive cardiogenic shock [76]. The Composite Pulmonary Embolism Shock score (CPES) has been developed to identify PE patients with normotensive shock [77]. CPES includes markers of RV function and ischemia, central thrombus burden, potential additional thrombus embolization (eg, from deep venous thrombosis), and cardiovascular compensation (tachycardia). Further evaluation is needed before CPES can be routinely used.

Timing — In general, clinicians have time to discuss relevant options with the patient and with other experts (eg, interventional radiology, pulmonary/critical care, cardiology, or cardiothoracic/vascular surgery). Factors that weigh into the decision process, the value of PE response teams, and timing of thrombolysis are discussed above. (See 'Pulmonary embolism response team' above.)

In some cases when the indication is uncertain (eg, intermediate-risk without significant tachycardia or oxygen requirement or with a relative contraindication), some experts, including our group, observe the response to anticoagulation during the first 24 hours following the diagnosis. If the patient improves clinically during that time, we typically do not proceed with thrombolytic therapy. In contrast, if the patient has persistent or worsening signs of distress (eg, severe tachycardia, borderline blood pressure, and/or poor oxygenation and tissue perfusion) during that period, we may proceed with reperfusion therapy (systemic thrombolysis or catheter-directed therapy [CDT]) since the benefits likely outweigh the risk at that point.

Low bleeding risk — In patients with intermediate-risk PE in whom thrombolysis is thought to be beneficial (table 4), we suggest CDT (typically thrombolysis or suction embolectomy) rather than systemic therapy, provided the expertise is available. Systemic thrombolytic therapy is an alternative if local expertise is not available (see 'High-risk PE and low bleeding risk: Systemic full-dose thrombolysis' above). Clinical trials of low-dose systemic thrombolysis (ie, doses in the range utilized for CDT) are underway (NCT03988842).

Catheter-directed thrombolysis — Our preference for catheter-directed thrombolysis is based on our clinical experience and the likelihood of a lower risk of bleeding with this method of delivery compared with systemic agents. The lower bleeding risk is likely due to the lower total dose of agent administered (eg, 8 to approximately 24 mg when catheter-administered versus 50 to 100 mg for intravenous tissue-type plasminogen activator [tPA]). In addition, during catheter-directed thrombolysis, other mechanical interventions can be simultaneously performed to aid clot dissolution (eg, ultrasound) or mechanical removal (eg, suction embolectomy) [78]. Data that support this approach are discussed below. (See 'Efficacy' below.)

Administration

●Access sites and catheters – Typical access sites are internal jugular and femoral veins. Catheters are placed under fluoroscopic guidance with the patient supine.

Choosing how many catheters to place, whether a bolus of thrombolytic agent is administered before the infusion, and whether lysis should be combined with other clot removal procedures is individualized and dependent on the operator, their experience, and the location and volume of emboli. For example, the presence of a large central main pulmonary artery embolus and/or right atrial clot in transit might prompt suction embolectomy whereas catheter-directed thrombolysis may be more appropriate for peripheral emboli. If both central and peripheral thrombus are present, suction embolectomy and catheter-directed thrombolysis may be combined.

For thrombolytic infusions, one catheter is typically placed per affected lung (ie, two for bilateral PE and one for unilateral PE). Catheters are usually placed proximally in the main pulmonary artery. In addition, we prefer infusions with a short duration and low-dose agent to reduce the risk of bleeding. An example would be 1 mg/hour per lung over four to six hours (ie, 12 mg tPA [alteplase] total) [79].

●Anticoagulation – There are no universally accepted anticoagulation protocols for catheter-directed thrombolysis. We reduce the unfractionated heparin (UFH) infusion dose to 300 to 500 units/hour while infusing tPA. Following the infusion of tPA, we then hold the heparin for 30 minutes, remove the sheaths, and restart UFH at full dose (ie, weight-based protocol). Alternatively, if the patient is already receiving therapeutic low molecular weight heparin, no anticoagulant is needed during CDT.

●Follow-up – Follow-up after the infusion is similar to that described for systemic agents. (See 'Short-term follow-up (24 to 48 hours)' above.)

Efficacy — Data to support thrombolytic therapy in patients with intermediate-high-risk PE suggest that the administration of catheter-directed thrombolysis results in rapid and early improvement in indices of RV function and cardiopulmonary hemodynamics; however, the impact on mortality is less certain.

Several trials have examined catheter-directed thrombolysis in patients with intermediate-risk PE [16,26,40-43,79-89]:

●A 2023 meta-analysis of 44 mostly observational studies in patients with mixed intermediate and high-risk PE reported that compared with systemic thrombolysis, catheter-directed thrombolysis was associated with reduced risk of death (odds ratio [OR] 0.43, 95% CI 0.32-0.57), intracerebral hemorrhage (OR 0.44, 95% CI 0.29-0.64), and major bleeding (OR 0.61, 95% CI 0.53-0.7) [90]. Compared with anticoagulation, catheter-directed thrombolysis was also associated with decreased risk of death (OR 0.36, 95% CI 0.25-0.52) and similar rates of intracerebral hemorrhage or major bleeding.

●An older meta-analysis of 28 studies totaling 2135 patients, 53 percent of whom had intermediate-risk PE, reported significant improvement in cardiopulmonary hemodynamics with ultrasound-assisted catheter-directed thrombolysis (USAT) [41]. The in-hospital mortality was 2.9 percent, long-term mortality (30 days to 3 years) 4.1 percent, major bleeding 5.4 percent, and recurrent venous thromboembolism 0.2 percent.

Different modalities and regimens have been used. However, USAT is the most studied and utilized regimen:

●In the only randomized trial, 59 patients with intermediate-high-risk PE received either catheter-directed thrombolysis plus anticoagulation or anticoagulation alone (ULTIMA) [80]. The USAT regimen consisted of high-frequency ultrasound combined with 10 (one lung) to 20 mg (two lungs) of tPA infused over 15 hours. At 24 hours, USAT resulted in an improved RV/left ventricular (LV) ratio compared with conventional anticoagulation (mean difference 0.3 versus 0.03), which was maintained at 90 days but without a mortality benefit. There were no major bleeding events or intracranial hemorrhage (ICH) in either group.

●A different USAT regimen in the same population that consisted of high-frequency ultrasound combined with 10 mg of tPA infused over five hours resulted in a reduction in mean pulmonary artery pressure and an increase in cardiac index, with only one episode of access-site related bleeding [91]. Whether limited versions of USAT such as this should be routinely used in patients with intermediate-high-risk PE requires further study.

●In OPTALYSE, 101 patients with acute intermediate-high-risk PE were randomized to one of four tPA catheter-directed thrombolysis regimens: 4 mg/lung over two hours, 4 mg/lung over four hours, 6 mg/lung over six hours, and 12 mg/lung over six hours [79]. Each of the regimens significantly improved the RV/LV ratio (by approximately 24 percent) compared with baseline. In addition, tPA incrementally reduced the clot burden at 48 hours, ranging from 5 percent reduction in patients receiving 4 mg/lung over four hours to 26 percent reduction in those receiving 12 mg/lung over six hours. The overall bleeding rate was 4 percent, with one ICH in a patient given 4 mg/lung over four hours. There was no heparin control arm. Outcomes at one year showed sustained recovery of the RV/LV ratio as well as improvements in functional status and quality of life [92].

●In the SUNSET trial, 81 patients with intermediate-high-risk PE were randomized to receive either USAT or standard catheter-directed thrombolysis without ultrasound assistance [82]. There was no difference in thrombus score reduction between the groups, although there was one stroke and one vaginal bleed requiring transfusion in the USAT group.

Limited data have compared catheter-directed thrombolysis with reduced-dose systemic regimens. These data are discussed below [86]. (See 'Reduced-dose systemic thrombolytic therapy' below.)

Further research is ongoing.

Bleeding rates and other adverse effects — Among the major studies (totaling over 300 patients) that examined the efficacy of catheter-directed thrombolysis [42,79,80,91], rates of major bleeding ranged from 0 to 4 percent and rates of ICH were <1 percent, especially when newer devices were used. Although bleeding rates have not been directly compared, these rates are lower than those reported in studies of systemic agents. (See 'Catheter-directed thrombolysis' above.)

Other complications include infection of venipuncture sites, worsening hemodynamic instability, cardiac arrest, and death, as well as device-specific adverse effects. With evolving technology, the risk of catastrophic pulmonary artery perforation is rare but can lead to pericardial tamponade and life-threatening hemoptysis.

Suction/mechanical embolectomy — Newer suction devices have been shown to be successful, and their use is increasing [36,93-97]. In centers with expertise, it is preferred compared with catheter-directed thrombolysis given that it is likely associated with a lower risk of bleeding. However, data are limited. As examples:

●A randomized trial of 550 patients with intermediate-risk PE compared catheter-directed thrombolysis with suction/mechanical embolectomy using a large-bore retrieval system and reported that mechanical (ie, suction/aspiration) embolectomy resulted in lower rates of a composite endpoint (mortality, intracranial hemorrhage, major bleeding, clinical deterioration and/or escalation to bailout, and postprocedural intensive care unit admission and length of stay; win ratio 5.01, 95% CI 3.68-6.97) [98]. The outcome was largely driven by a significant improvement in clinical deterioration/bailout therapy (1.8 versus 5.4) and intensive care use (46 versus 99 percent), although most bailout procedures were managed in the procedure suite. At 24 hours, patients treated with mechanical embolectomy were less dyspneic and fewer had moderate or severe RV dysfunction (42 versus 58 percent). At 30 days, mortality remained similar (<1 percent) as were dyspnea scores. Readmissions within 30 days after mechanical embolectomy were lower compared with catheter-directed thrombolysis (3.2 versus 7.9 percent), although PE-related admissions were similar (0 versus 0.8 percent).

●In a study (FLARE) of 106 patients with intermediate-risk PE, suction embolectomy improved RV function and pulmonary artery pressure with a complication rate of only 4 percent [93]. There was one major bleed.

●In a retrospective study, use of a flow-retrieval suction device reported improved in-hospital mortality and decreased intensive care unit length of stay for patients with acute central PE [36].

Alternatives — Alternatives should be considered when CDT is not available.

Systemic full-dose thrombolytic therapy — Limited data support full-dose systemic thrombolytic in patients with intermediate-risk PE.

●As described above, in a 2021 meta-analysis of 29 studies of patients with acute PE (high- and intermediate-risk PE), compared with heparin alone, thrombolysis resulted in a reduction in mortality (odds ratio [OR] 0.57, 95% CI 0.37-0.87; 2.8 versus 4.9 percent; 30 to 6 fewer deaths) but at the expense of major bleeding (OR 2.9, 95% CI 1.95-4.31; 10.4 versus 3.8 percent; 33 to 107 more events) [3]. There were no major differences in relative mortality benefit or odds of major bleeding in intermediate-risk versus mixed intermediate- and high-risk patients. Data describing full-dose systemic thrombolytic therapy in mixed populations of high- and intermediate-risk PE are discussed above (See 'Efficacy' above.)

●One randomized trial (PEITHO) compared systemic thrombolytic therapy (tenecteplase) plus heparin with placebo plus heparin in 1005 patients with acute intermediate-high-risk PE [26]. Tenecteplase was administered as an intravenous push with weight-based dosing (30 mg for ≤60 kg, 35 mg for 61 to 69 kg, 40 mg for 70 to 79 kg, 45 mg for 80 to 89, 50 mg for ≥90 kg). Thrombolysis resulted in a reduction in hemodynamic decompensation (1.6 versus 5 percent) and a numeric (but not statistically significant) decrease in mortality (1.2 versus 1.8 percent at 7 days, 2.4 versus 3.2 percent at 30 days). The administration of tenecteplase was associated with increased extracranial bleeding (6 versus 1 percent), major bleeding (12 versus 2 percent), and hemorrhagic stroke (2 versus 0.2 percent). In a prespecified subgroup analysis of patients >75 years of age, benefits of therapy were maintained but rates of extracranial bleeding were higher (11 versus 0.6 percent), suggesting that risk-benefit may be more favorable in those ≤75 years. Long-term follow-up also suggested similar outcomes [25].

Reduced-dose systemic thrombolytic therapy — Based on the rationale that reduced doses of a thrombolytic agent may be sufficient to lyse clot effectively while minimizing the risk of bleeding, several trials have examined the efficacy and safety of reduced doses of systemic thrombolytic agents in patients with acute PE [23,86,99-102]. However, data are insufficiently robust to make a recommendation to routinely implement this as a first-line regimen for any category of PE patients.

●The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial examined reduced-dose intravenous tPA (alteplase) compared with heparin alone [23]. This dose of tPA was ≤50 percent of the standard dose (100 mg) for patients weighing ≥50 kg and 0.5 mg/kg for those weighing <50 kg. At 28 months, low-dose tPA resulted in lower pulmonary pressures, faster resolution of pulmonary pressures, and nonsignificant lower rates of recurrent PE (0 versus 5 percent) and mortality (1.6 versus 5 percent). There were no major bleeding events in either group. However, there was a low prevalence of RV dysfunction (<25 percent) and RV hypokinesis (<7 percent) such that applicability to patients with intermediate-high-risk PE is limited.

●One randomized trial of 118 patients with acute PE, two-thirds of whom had significant pulmonary artery obstruction and RV dysfunction (ie, intermediate-high-risk PE) and one-third of whom had high-risk PE, compared low-dose intravenous tPA (50 mg) with full-dose tPA (100 mg). Low-dose tPA resulted in a lower mortality rate (2 versus 6 percent) and bleeding rate (3 versus 10 percent) [100].

●A retrospective database study of patients with PE undergoing thrombolysis (both high- and intermediate-risk) reported that patients treated with one-half-dose alteplase (50 mg) required less vasopressor therapy and invasive ventilation but needed therapy escalation more often than patients treated with full-dose alteplase (tPA 100 mg) [99]. Hospital mortality and rates of significant bleeding were similar.

●Another retrospective analysis of patients with high- and intermediate-risk PE compared half-dose systemic thrombolysis with USAT and found that both therapies led to similar reductions in the pulmonary artery systolic pressure and RV/LV ratio but half-dose thrombolysis also reduced the duration and cost of hospitalization [86].

●A case study of four patients with intermediate-risk PE reported successful use of "ultra" low-dose and slow infusion of tPA (25 mg at 1 mg/hour), with all four patients demonstrating improved hemodynamics within hours of administration [101].

High bleeding risk — Options in this population are limited to mechanical catheter-directed thrombus removal (eg, suction embolectomy) with or without limited application of thrombolytic agent, persisting with anticoagulation (if bleeding risk allows), or an inferior vena cava (IVC) filter. Surgical embolectomy is not typically an option since the risk of surgery is so high and the indication is weak. The exception is when clot-in-transit is seen. Choosing among the options is limited by available expertise. (See 'Catheter-directed therapies (CDTs)' above.)

SPECIAL POPULATIONS

Cardiopulmonary resuscitation — Thrombolytic therapy should not be routinely administered in patients during cardiac arrest. However, the decision to administer treatment as a potentially lifesaving maneuver for suspected PE-induced cardiac arrest (or impending arrest) can be considered on a case-by-case basis. Another option for PE treatment during cardiac arrest includes anticoagulation and use of extracorporeal membrane oxygenation (ECMO). (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Hemodynamic support' and "Extracorporeal life support in adults: Management of venoarterial extracorporeal membrane oxygenation (V-A ECMO)", section on 'Acute decompensated pulmonary vascular disease'.)

Efficacy — Case series have reported some success from systemic thrombolytic therapy during cardiopulmonary resuscitation (CPR) when the cardiac arrest is due to suspected or confirmed acute PE [103-106]. Thrombolysis may be more successful when there is intermittent recovery during CPR and less successful in refractory pulseless electrical activity (PEA) arrest.

●In a retrospective study of patients with out-of-hospital cardiac arrest, patients who were treated with thrombolysis prehospitalization ("mobile intensive care unit") and found subsequently to have confirmed PE had a higher 30-day survival compared with patients who did not receive thrombolysis [106].

●One retrospective study reported a 5 percent incidence of PE (diagnosed by autopsy, clinically, or echocardiography) in 1246 cardiac arrest patients [104]. Subgroup analysis suggested that thrombolysis was associated with a greater rate of return of spontaneous circulation (ROSC) compared with those who did not receive thrombolysis.

●Another retrospective study of 23 patients with PEA due to confirmed massive PE reported ROSC within 2 to 15 minutes after the administration of tissue-type plasminogen activator (tPA; alteplase) at a reduced dose of 50 mg intravenous push [105].

●In contrast, another randomized study of 233 patients who presented with PEA arrest of unknown etiology reported that thrombolysis did not improve survival or ROSC compared with placebo [107].

Data regarding thrombolysis in sudden cardiac arrest not due to PE are discussed in more detail separately. (See "Therapies of uncertain benefit in basic and advanced cardiac life support", section on 'Fibrinolysis'.)

Dosing (bolus injections) — During a cardiac arrest or impending cardiac arrest, it is more practical to give tPA (alteplase) as an intravenous bolus using an entire 50 mg vial over two minutes rather than preparing an infusion to be administered over two hours, which is typical for noncardiac arrest patients. The bolus can be repeated after 15 minutes in the absence of ROSC. This regimen is generally consistent with American Heart Association guidelines on CPR and with the American College of Chest Physicians guidelines on antithrombotic therapy for venous thromboembolism [2,108,109].

If tPA alteplase is unavailable, but tenecteplase is available, a single dose of intravenous tenecteplase given over five seconds can be given for PE-related cardiac arrest based on patient weight as follows [110,111]:

●<60 kg – 30 mg

●≥60 to <70 kg – 35 mg

●≥70 to <80 kg – 40 mg

●≥80 to <90 kg – 45 mg

●≥90 kg – 50 mg

In general, thrombolytic therapy for patients with PE-related cardiac arrest is given with systemic anticoagulation (eg, unfractionated heparin infusion); in other words, the anticoagulant is not withheld [108]. (See 'Anticoagulation before thrombolysis' above.)

Clot-in-transit — Some patients present with a free-floating right atrial or right ventricle (RV) thrombus or thrombus in a patent foramen ovale (PFO) or IVC. Options in this population include anticoagulation alone, thrombolysis, catheter- or surgical-based clot removal, or surgical embolectomy. Limited data support choosing one option over another.

We prefer an individualized approach that involves expert consultation and assessment of factors including thrombus size and location and consequence of embolization. For example, patients with large thrombus in the right atrium or RV may be candidates for catheter-directed extraction; systemic thrombolysis or surgical thrombectomy is an alternative. In contrast, patients with smaller thrombi may be simply anticoagulated. Patients with a large thrombus who also have a PFO may be better suited to surgical removal and closure of the PFO (at a later date). Occasionally, venoarterial ECMO is needed for hemodynamic stability during extraction. (See 'Pulmonary embolism response team' above and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults".)

Data are limited; retrospective reports suggest that outcomes may be similar with anticoagulation and reperfusion therapies, at least among patients with evidence of right heart thrombus [112-114]. Another retrospective study of patients with clot-in-transit reported that only 20 percent received advanced therapy in combination with anticoagulation [115]; large thrombus size and high body mass index predicted worse outcomes.

Pregnancy — Thrombolysis is relatively contraindicated in patients who are pregnant but should be strongly considered in high-risk PE. Further details are provided separately. (See "Venous thromboembolism in pregnancy and postpartum: Treatment", section on 'Thrombolysis/thrombectomy'.)

SOCIETY GUIDELINE LINKS — 

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

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th 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 10^th to 12^th 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.)

●Beyond the Basics topics (see "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient education: Pulmonary embolism (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Making the decision – Thrombolytic therapy is mostly administered to select patients with confirmed acute pulmonary embolism (PE). A multidisciplinary approach (eg, PE response team) should integrate several clinical factors that stratify the risk of death from acute PE (low, intermediate, high risk) (table 1 and table 3 and table 4) and the risk of bleeding from the agent (table 2). (See 'Making the decision' above.)

●High-risk PE and low risk of bleeding – Patients with high-risk PE are those with unstable hypotension (defined in the legend of the table (table 1)), shock, or cardiac arrest due to PE. Our approach is the following (see 'High-risk PE and low bleeding risk: Systemic full-dose thrombolysis' above):

•For patients with high-risk PE (first or recurrent event) who are at low risk of bleeding, we recommend systemic thrombolytic therapy followed by anticoagulation, rather than anticoagulation alone (Grade 1B) (table 3).

Limited data demonstrate a faster resolution of thrombus and cardiopulmonary hemodynamics and a mortality benefit compared with heparin. However, the benefit may vary with the strength of the indication and occurs at the expense of an increased risk of major bleeding, which can sometimes be catastrophic. (See 'Efficacy' above and 'Bleeding rates' above.)

•Recombinant tissue plasminogen activator (tPA; eg, alteplase 100 mg) is the most common agent used, typically administered over ≤2 hours. Clinical improvement is typically noted within the first hour. Signs of major bleeding are indications to immediately stop the infusion and investigate, locate, and treat the source (eg, hemodynamic compromise, mental status changes, reduction in hemoglobin [eg, 1 to 2 g/dL], need for transfusion, and copious amounts of bleeding). Anticoagulation is typically held during and restarted after the infusion when the activated partial thromboplastin time is less than twice the upper limit of normal. (See 'Administration' above.)

●High-risk PE and high risk of bleeding – For patients with high-risk PE who are at high risk of fatal bleeding or have other contraindications to systemic thrombolysis (table 2), we suggest catheter-directed therapy (CDT) rather than surgical embolectomy (Grade 2C). CDT examples include suction embolectomy or catheter-directed low-dose thrombolysis (with or without ultrasound); choosing among these is individualized. (See 'High-risk PE and high bleeding risk: Catheter-directed therapies' above.)

Evidence to support this approach is derived from limited and indirect data from patients with intermediate- and high-risk PE who are at low risk of bleeding as well as the presumptive lower procedural risk associated with catheter-directed techniques when compared with surgical embolectomy. (See 'Catheter-directed thrombolysis' above.)

Surgical embolectomy may be the only option when catheter-directed techniques are not available. (See 'Alternatives' above.)

●Intermediate-risk PE and low risk of bleeding – These patients have imaging and/or biochemical evidence of right ventricular (RV) dysfunction (table 4).

•Anticoagulation – For patients with intermediate-low risk PE or intermediate-high risk PE without additional concerning features (table 1 and table 3), we suggest anticoagulation alone rather than CDTs or thrombolysis (Grade 2C). These patients have very low rates of mortality or long-term morbidity due to PE with anticoagulation alone, so this strategy avoids bleeding and perioperative risk. Anticoagulation in those at low-risk of bleeding is managed similarly to those with low-risk PE. (See "Acute pulmonary embolism in adults: Treatment overview and prognosis", section on 'Anticoagulation'.)

•Reperfusion – Patients at the highest risk of death from PE may be candidates for reperfusion therapy. The approach is individualized. Our approach is as follows:

For patients with intermediate-high-risk PE (ie, both biochemical and imaging evidence of RV dysfunction) (table 1 and table 3) with a concerning prognosis due to one or more of the following features, we suggest reperfusion therapy rather than anticoagulation alone (Grade 2C):

-Worsening hypotension (not meeting "high-risk" criteria)

-Severe or worsening respiratory distress or hypoxemia

-Worsening or persistent tachycardia >120 beats per minute

-Right-sided thrombus in transit

-Syncope

-Elevated lactate

Some patients may be determined not to be at increased risk for mortality from PE despite having one or more of these features due to individual patient factors (eg, comorbidities explaining a feature) or reassuring aspects of their clinical course. In contrast, patients with initially low- or intermediate-risk PE who deteriorate and develop these higher-risk features while on anticoagulant therapy may be good candidates for this reperfusion-based approach. (See 'Low bleeding risk' above and 'Rationale for reperfusion and patient selection' above.)

In terms of specific interventions for this group, we suggest CDTs (eg, catheter-directed thrombolysis and/or suction) rather than systemic thrombolysis or anticoagulation alone (Grade 2C), provided these therapies are available. Our preference for CDT is based on our clinical experience, more rapid resolution of pulmonary hemodynamics compared with heparin, and a likely lower risk of bleeding with CDT compared with systemic agents. Catheter-directed suction embolectomy is being increasingly used due to the likely lower risk of bleeding compared with systemic or catheter-directed thrombolysis. (See 'Efficacy' above and 'Bleeding rates and other adverse effects' above.)

If local expertise is not available, full- or reduced-dose systemic thrombolytic therapy are reasonable alternatives. (See 'Catheter-directed thrombolysis' above and 'Alternatives' above.)

●Intermediate-risk PE and high risk of bleeding – For patients with intermediate-risk PE who have a high risk of bleeding, options are limited to catheter-directed suction embolectomy, persisting with anticoagulation (if bleeding risk allows), or an inferior vena cava filter. Surgical embolectomy is not typically an option unless clot-in-transit is seen. Choosing among the options is limited by available expertise. (See 'High bleeding risk' above.)

●Special populations – Thrombolytic therapy in select populations requiring an individual approach includes the following (see 'Special populations' above):

•Patients with cardiac arrest – (See 'Cardiopulmonary resuscitation' above.)

•Patients with thrombus-in-transit – (See 'Clot-in-transit' above.)

•Pregnant patients – (See 'Pregnancy' above and "Venous thromboembolism in pregnancy and postpartum: Treatment", section on 'Patients with life-threatening thrombosis'.)

ACKNOWLEDGMENT — 

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