Contemporary Treatment of Pulmonary Embolism: Medical Treatment and Management

Abstract

Pulmonary embolus (PE) is defined as obstruction of the pulmonary artery or one of its branches by material (e.g., thrombus, tumor, air, or fat) but most commonly due to thrombus originating from the lower extremity deep veins.

We reviewed the current literature describing the optimal medical treatment and management of PE.

Databases (PubMed, the Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL) were searched for relevant studies and guidelines for management of patients with PE.

The initial approach to patients with suspected PE should focus upon stabilizing the patient while further workup for risk stratification is in progress. In most cases, anticoagulation should ideally be started even prior to confirming PE, if risk–benefit regarding suspicion of PE and bleeding risk is favorable.

Once the diagnosis is confirmed, risk stratification will guide further therapies consisting of anticoagulation, thrombolysis, or catheter-directed interventions. Data for initial, long-term, and indefinite anticoagulation, and factors that determine whether or not a patient can be treated in the outpatient setting, are reviewed and discussed.

Pulmonary embolism (PE) is an important cause of morbidity and mortality with more than 300,000 U.S. cases annually and as many as 25% of patients presenting with sudden death. ¹ The 2019 U.S. national data showed that 37,571 deaths resulted from PE. ¹ During the ongoing coronavirus disease (COVID) pandemic, the incidence of venous thromboembolism (VTE) was up to 31% in hospitalized patients with a two- to threefold greater risk of developing deep vein thrombosis (DVT) or PE among those who were admitted to the intensive care unit. Furthermore, PE is associated with increased mortality rates for up to 3 months after the index PE event. PE is a disease spectrum with varying clinical severity ranging from an incidental finding to obstructive shock from right heart failure. In this review article, we examine contemporary optimal medical management of PE including type and duration of anticoagulation therapy.

Initial Management Strategy

The initial approach to patients with suspected PE should focus upon stabilizing the patient while workup is in progress. Anticoagulation therapy is the single most important treatment and should ideally be started even prior to confirming PE, if risk–benefit regarding suspicion of PE and bleeding risk is favorable. Early therapeutic anticoagulation (goal activated partial thromboplastin time within 24 hours) is associated with up to 70% decreased risk for mortality in patients with PE. ²

Pulmonary Embolism Response Teams

The main objective of pulmonary embolism response teams (PERTs) is to provide the best advanced therapeutic options available in a case-by-case individual clinical scenario; streamlining care, in an efficient, fast, and in a multidisciplinary, multispecialty communication, and teamwork manner for the referring physician. By allowing rapid multidisciplinary, multispecialty evaluation, assessment, and mobilization of institutional resources, PERT may have a positive impact on outcomes and survival in the severest forms of acute PE. ^{3 4 5 6} During the COVID pandemic, PERT should help further aid and facilitate smooth transfer of care in patients with concomitant COVID-19 and acute PE, providing recommendations of type of anticoagulation, dose of medications, length of therapy, and prompt follow-up in a designated thrombosis/vascular medicine once discharged from the hospital.

Anticoagulation

Anticoagulant therapy is indicated for patients with PE unless contraindicated with initial anticoagulant therapy administered as soon as possible to rapidly achieve therapeutic anticoagulation. For patients with intermediate or high-risk PE, unfractionated heparin (UFH) should be considered as the preferred agent, as it allows for faster off-set of anticoagulation in case of bleeding and if thrombolysis, catheter-based interventions or mechanical circulatory support are being considered. ⁷ For most patients with PE who are hemodynamically stable and do not show signs of right ventricular (RV) dysfunction, significant renal impairment, or severe obesity, subcutaneous low molecular weight heparin (LMWH) or fondaparinux, or the oral factor Xa inhibitors, rivaroxaban, or apixaban are recommended. In those patients, LMWH is recommended over UFH, since LMWH is associated with reduced incidence of recurrent VTE and bleeding risk. ⁸ Subcutaneous fondaparinux is a safe and effective alternative to heparin in the early treatment of acute PE. ⁹ Currently, rivaroxaban and apixaban are the only direct oral anticoagulants (DOACs) approved by regulatory agencies as monotherapy and pretreatment with heparin is not necessary for the treatment of PE with these agents. Within the DOAC family, new evidence suggests that the use of apixaban is associated with lower rates of bleeding and recurrent VTE when compared with rivaroxaban. ¹⁰ If dabigatran, or the factor Xa inhibitor edoxaban is used, a short course of heparin (typically LMWH) should be administered for 5 days prior to transitioning to oral therapy with these agents. See Table 1 for details on DOAC therapies in patients with PE. It is important to keep in mind that medication adherence to long-term DOAC therapy outside of clinical trials is low and can be associated with significant adverse effects. ¹¹ In general, all patients are anticoagulated for a minimum of 3 months after an acute event, but treatment duration should be individualized based on the patient's risk factors and bleeding risk. Some patients with unprovoked PE or those with persistent risk factors are candidates for indefinite anticoagulation and depends upon the nature of the event. In patients on long-term anticoagulation, the duration of anticoagulation should be reassessed annually. It is important to note, that in patients with a first unprovoked VTE, the risk for VTE recurrence after discontinuation of anticoagulation increases over time. ¹² Selected low-risk patients with PE can be treated with outpatient therapy after giving the first dose of anticoagulant in the hospital, with the remaining doses given at home. Patients appropriate for outpatient therapy should be clinically stable with good cardiopulmonary reserve, have no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (i.e., < 50,000/mm ³ ), expected to be compliant with treatment, and feel well enough to be treated at home.

Table 1. Direct-acting oral anticoagulants (DAOCs) trials in patients with pulmonary embolism.

Trial	AC	Total number of patients with VTE	Patients with PE	Recurrent VTE N (%)	Major bleed N (%)
RE-COVER 36	Dabigatran	1,273	31%	30 (2.4) 27.1 (2.1)	20 (1.6) 24 (1.9)
	Warfarin	1,266	31%
RE-COVER II 37	Dabigatran	1,280	31%	30 (2.3) 28 (2.2)	15 (1.2) 22 (1.7)
	Warfarin	1,288	32%
EINSTEIN-PE 38	Rivaroxaban	2,419	100%	50 (2.1) 44 (1.8)*	26 (1.1) 52 (2.2)*
	LMWH + VKA	2,413	100%
Hokusai-VTE 39	Edoxaban	4,118	40%	130 (3.2) 146 (3.4)*	56 (1.4) 66 (1.6)
	Warfarin	4,122	41%
AMPLIFY 40	Apixaban	2,691	34%	59 (2.3) 71 (2.7)*	15 (0.6) 49 (1.8)*
	LMWH + VKA	2,704	33%
Dawwas et al 10	Apixaban	18,618	Not specified	475 (2.6)	386 (2.1)
	Rivaroxaban	18,618	Not specified	595 (3.2)	577 (3.1)

Abbreviations: *A statistically significant difference between the groups. AC, anticoagulation; AMPLIFY, Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism; LMWH, low molecular weight heparin; PE, pulmonary embolism; RE-COVER , Efficacy and Safety of Dabigatran Compared with Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism; RE-COVER II, Phase III Study Testing Efficacy & Safety of Oral Dabigatran Etexilate vs. Warfarin for 6 Month Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; EINSTEIN-PE Study, Treatment for Acute Symptomatic Venous Thromboembolism (VTE); VKA, vitamin K antagonists; VTE, venous thromboembolism.

Thrombolytic Therapy

Outcomes following acute PE depend on the individual patient's cardiac reserve and the ability of the RV to cope with increased afterload caused by vascular obstruction. The clinical presentation of acute PE is highly variable and the clinical course of patients with PE encompasses a wide variety of clinical severities, ranging from asymptomatic to sudden death. In general, thrombolytic therapy is associated with reduced cardiovascular collapse from right heart failure at the cost of increased major bleeding risk. Thrombolytic therapy is currently recommended in patients with high-risk or massive PE who are not at high bleeding risk. High-risk PE is currently defined as acute PE associated with hypotension (systolic blood pressure [BP] < 90 mm Hg for at least 15 minutes), or a drop of at least 40 mm Hg of systolic BP on the same day, signs of shock, or respiratory distress. ¹³ In high-risk or massive PE, thrombolytic therapy should be administered through a peripheral intravenous line due to its fast availability. Guidelines that recommend systemic thrombolytic therapy in high-risk or massive PE are the American Heart Association, ¹⁴ American College of Chest Physicians, ¹⁵ the PERT Consortium, ⁷ and the European Society of Cardiology. ¹³

Thrombolytic therapy may be considered in selected patients with submassive PE with high-risk features and low bleeding risk. Submassive or intermediate high-risk PE is currently defined as acute PE not associated with hypotension but with multiple signs of RV dysfunction, evidence of clinical deterioration such as increasing tachycardia, shock index, tachypnea, hypoxia, and transient decrease in systolic BP. RV dysfunction can be detected on echocardiogram (RV dilation, RV sys dysfunction, increased tricuspid regurgitation, RV free wall hypokinesis), computed tomography scan (RV diameter divided by left ventricular diameter > 0.9), elevation of N-terminal pro-brain natriuretic peptide, or elevated serum troponin levels. ¹³ Submassive PE with high-risk features represents a fundamentally heterogeneous group of patients that are clinically challenging and require highly individualized risk–benefit assessment in regards to thrombolytic therapies. In a meta-analysis of 16 randomized studies comparing thrombolytic therapy with anticoagulation therapy in patients with submassive PE (hemodynamically stable patients with RV dysfunction), we found that thrombolytic therapy, as compared with standard anticoagulant therapy, reduced mortality by 47% but was associated with a 2.7-fold increase in major bleeding. ¹⁶ Furthermore, the rate of major bleeding was not significantly increased with thrombolysis for those < 65 years, but tripled in the subgroup of patients ≥ 65 years. Several risk scores such as BACS ¹⁷ and PE-SARD can be used to estimate an individual patient's risk for major bleeding after systemic thrombolysis. It is important to note that the ideal dosing of systemic thrombolytic therapy for acute intermediate risk or submassive PE is unknown. Higher doses of thrombolytic therapy are inevitably associated with higher bleeding risk, whereas “lower-dose” regimens might yield similar clinical efficacy with substantially lower bleeding risk. ¹⁸ The evidence around reduced-dose systemic thrombolysis needs to solidify before dosing recommendations can be made. Furthermore, some guidelines recommend to overlap thrombolysis and heparin anticoagulation, which might be associated with an increased risk of bleeding. ¹³ Although commonly used thrombolytics have a short half-life, the effects on the coagulation pathway can be prolonged. ^{19 20} In addition, there is great individual variability in the response to systemic thrombolysis making it difficult for the clinician to predict bleeding risk. ^{21 22} Currently, there is no high-quality evidence to guide monitoring of coagulation after administration of systemic thrombolysis, an area where more clinical research is desperately needed.

The 2021 American College of Chest Physicians guidelines recommend thrombolytic therapy for PE with hemodynamic instability (systolic BP < 90 mm Hg) or those who clinically deteriorate based on the factors mentioned above. ¹⁵ See Table 2 for details on thrombolytic therapy for acute PE.

Table 2. Thrombolysis trials in pulmonary embolism.

Study	tPA dose	Major bleeding rate [%]
A Randomized Trial of a Single Bolus Dosage Regimen of Recombinant Tissue Plasminogen Activator in Patients with Acute Pulmonary Embolism, Levine et al 1990 41	tPA 0.6 mg/kg bolus	0
Tissue plasminogen activator for the treatment of acute pulmonary embolism. A collaborative study by the PIOPED Investigators, 1990 42	40–80 mg at 1 mg.min	11.1
Alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2 (PAIMS2), Dalla-Volta et al 1992 43	tPA 100 mg over 2 hours	15
Alteplase versus heparin in acute pulmonary embolism: Randomized trial assessing right ventricular function and pulmonary perfusion, Goldhaber et al 1993 44	tPA 100 mg over 2 hours	2.2
Reduced Dose Bolus Alteplase vs Conventional Alteplase Infusion for Pulmonary Embolism Thrombolysis: An International Multicenter Randomized Trial, Goldhaber et al 1994 45	tPA 0.6 mg/kg over 15 minutes	3.3
Hemodynamic effects of bolus vs 2-hour infusion of alteplase in acute massive pulmonary embolism. A randomized controlled multicenter trial, Sors et al 1994 46	tPA 0.6 mg/kg over 15 minutes	8
Streptokinase vs alteplase in massive pulmonary embolism. A randomized trial assessing right heart haemodynamics and pulmonary vascular obstruction, Meneveau et al 1997 47	tPA 100 mg over 2 hours	16
Hemodynamic effects of double bolus reteplase versus alteplase infusion in massive pulmonary embolism, Tebbe et al 1999 48	tPA 100 mg over 2 hours	31
Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism (MAPPET), Konstantinides et al 2002 49	Alteplase 100 mg over 2 hours	0.8
Bolus tenecteplase for right ventricle dysfunction and hemodynamically stable patients with pulmonary embolism, Becattini et al 2010 50	Tenecteplase 30 to 50 mg bolus	7.1
Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial, Wang et al 2010 18	tPA 50 mg over 2 hours	3.6
Six-month echocardiographic study in patients with submassive pulmonary embolism and right ventricle dysfunction: comparison of thrombolysis with heparin, Fasullo et al 2011 51	tPA 100 mg over 2 hours	5.4
Moderate Pulmonary Embolism Treated With Thrombolysis, Sharifi et al 2013 52	tPA 50 mg over 2 hours	0
Treatment of submassive pulmonary embolism with tenecteplase or placebo: Cardiopulmonary outcomes at 3 months: Multicenter double-blind, placebo controlled randomized trial (TOPCOAT), Kline et al 2014 53	Tenecteplase 30 to 50 mg bolus	2.5
Fibrinolysis for Patients with Intermediate- Risk Pulmonary Embolism (PEITHO), Meyer et al 2014 54	Tenecteplase 30–50 mg bolus	2.0
Thrombolysis With Single Bolus Tenecteplase Compared With Streptokinase Infusion in the Treatment of Acute Pulmonary Embolism: A Pilot Study, Patra et al 2015 55	Tenecteplase 30–50 mg bolus	0
Half dose versus full dose alteplase for treatment of pulmonary embolism, Kiser et al 2018 56	tPA 50 mg over 6 hours	2

Abbreviation: tPA, tissue plasminogen activator.

2021 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

The key recommendations form the 2021 CHEST Expert Panel Report on antithrombotic therapy for PE is summarized below. ¹⁵

• In patients with subsegmental PE (no involvement of more proximal pulmonary arteries) and no proximal DVT in the legs who have a (1) low risk for recurrent VTE, the guidelines suggest clinical surveillance over anticoagulation and for (2) high risk for recurrent VTE, guidelines suggest anticoagulation over clinical surveillance.

• In patients who are incidentally found to have asymptomatic PE, the guidelines suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic PE.

• In patients with acute PE associated with hypotension (e.g., systolic BP < 90 mm Hg) who do not have a high bleeding risk, the guidelines suggest systemically administered thrombolytic therapy over no such therapy.

• In most patients with acute PE not associated with hypotension, the expert panel recommends against systemically administered thrombolytic therapy.

• In selected patients with acute PE who deteriorate (decrease in systolic BP, increase in heart rate, worsening gas exchange, signs of inadequate perfusion, worsening RV function, or increasing cardiac biomarkers) after starting anticoagulant therapy but have yet to develop hypotension and who have an acceptable bleeding risk, the guidelines suggest systemically administered thrombolytic therapy over no such therapy.

• In patients with low-risk PE the guidelines recommend outpatient treatment over hospitalization-provided access to medications, ability to access outpatient care, and home circumstances are adequate. Patients who satisfy all the following criteria are suitable for treatment of acute PE out of the hospital: (1) clinically stable with good cardiopulmonary reserve; (2) no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (i.e., < 50,000/mm ³ ); (3) expected to be compliant with treatment; and (4) the patient feels well enough to be treated at home.

• In patients with VTE (DVT of the leg or PE) the guidelines recommend apixaban, dabigatran, edoxaban, or rivaroxaban over vitamin K antagonist (VKA) as treatment-phase (first 3 months) anticoagulant therapy.

• In patients with confirmed antiphospholipid syndrome being treated with anticoagulant therapy, the guidelines suggest adjusted-dose VKA (target international normalized ratio [2.5) over DOAC therapy during the treatment phase.

• In patients with VTE (DVT and PE) diagnosed in the absence of transient provocation (unprovoked VTE or provoked by persistent risk factor), the guidelines recommend offering extended-phase anticoagulation with a DOAC.

• In patients offered extended-phase anticoagulation, the 2021 guidelines suggest the use of reduced-dose apixaban or rivaroxaban over full-dose apixaban or rivaroxaban. Reduced dose refers to apixaban 2.5 mg twice daily and rivaroxaban 10 mg once daily.

Special Populations

Malignancy and PE

In most patients with PE and malignancy who do not have severe renal insufficiency (e.g., creatinine clearance < 30 mL/minute), DOAC, apixaban or rivaroxaban (as monotherapy), or edoxaban (after a 5-day course of LMWH) or LMWH is recommended. Randomized studies have reported similar rates of recurrence with apixaban and edoxaban when compared with LMWH. ^{23 24} Randomized studies have demonstrated superiority of LMWH compared with VKA in patients with VTE in association with active cancer ²⁵ and several trials have shown comparable efficacy of LMWH and DOACs. ^{24 26 27} Based on these data LMWH and DOACs are preferred to VKAs for anticoagulation in malignancy-associated PE.

Pregnancy and PE

Pregnancy increases the risk for DVT as well as PE, and adjusted-dose subcutaneous LMWH is preferred over adjusted-dose intravenous or subcutaneous UFH. VKAs, oral direct thrombin inhibitors (e.g., dabigatran), or anti-Xa inhibitors (e.g., rivaroxaban, apixaban) are not recommended as VKAs cross the placenta, may be teratogenic, and may lead to fetal hemorrhage and due to paucity of data regarding safety during pregnancy with direct thrombin or factor Xa inhibitors. In general, anticoagulant therapy should continue at least 6 weeks postpartum with a total duration of anticoagulant therapy of at least 3 to 6 months for those with transient risk factors for VTE, that is, pregnancy.

Heparin-Induced Thrombocytopenia Patient with PE

There are several nonheparin anticoagulants that can be used in a patient with heparin-induced thrombocytopenia (HIT) with PE. These include parenteral direct thrombin inhibitors (e.g., argatroban, bivalirudin), fondaparinux, or DOACs such as apixaban, edoxaban, rivaroxaban, or dabigatran. Several observational studies have reported that DOACs that directly target thrombin (dabigatran) or factor Xa (e.g., apixaban, edoxaban, rivaroxaban) are effective in reducing thrombosis risk in HIT, without stimulating HIT antibodies. ^{28 29 30 31}

Contraindication to Anticoagulation

An inferior vena cava filter is indicated for patients with acute proximal DVT and PE who have an absolute contraindication to anticoagulant therapy such as recent major surgery, hemorrhagic stroke, or those with active bleeding. ³²

COVID-19 and PE

Infection with COVID-19 predisposes patients to thrombotic disease both in the venous and arterial circulation. Available data suggests that in the absence of a contraindication, acutely ill hospitalized patients with COVID-19 must receive pharmacological thromboprophylaxis, preferably with LMWH. ³³ Therapeutic anticoagulation is mainstay in the management of patients with PE, with an individual agent and dose based on renal or hepatic dysfunction, thrombocytopenia, and gastrointestinal tract function. ³⁴ LMWH is usually the first-line treatment with intravenous UFH preferred for patients with severe renal impairment, or in those that need invasive procedures. ³⁵ DOACs may be used only after the acute phase in stable patients.

Conclusion

PE is an important cause of morbidity and mortality in the U.S. and globally. The initial approach to patients with suspected PE should focus upon stabilizing the patient with anticoagulation the cornerstone for therapy. Thrombolysis is indicated in only a select group with hemodynamic instability or in those who deteriorate after initial anticoagulation and develop decrease in systolic BP, worsening gas exchange, signs of inadequate perfusion, worsening RV function, or increasing cardiac biomarkers. Finally, PERTs may streamline and optimize care of these individuals who are at high risk of morbidity and mortality.