Pulmonary embolism overview

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Editor(s)-In-Chief: The APEX Trial Investigators, C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Overview

Pulmonary embolism (PE) is an acute obstruction of the pulmonary artery (or one of its branches).

The obstruction in the pulmonary artery that causes a PE can be due to thrombus, air, tumor, or fat. Most often, this is due to a venous thrombosis (blood clot from a vein), which has been dislodged from its site of formation in the lower extremities. It has then embolized to the arterial blood supply of one of the lungs. This process is termed thromboembolism.

PE is a potentially lethal condition. The patient can present with a range of signs and symptoms, including dyspnea, chest pain while breathing, and in more severe cases collapse, shock, and cardiac arrest.

PE treatment requires rapid and accurate risk stratification before the development of hemodynamic collapse and cardiogenic shock. Treatment consists of an anticoagulant medication, such as heparin or warfarin, and in severe cases, thrombolysis or surgery.

Pulmonary embolism can be classified based on the time course of symptom presentation (acute and chronic) and the overall severity of disease (stratified based upon three levels of risk: massive, submassive, and low-risk).

Classification Based on Acuity and Size

Acute Pulmonary Embolism

A pulmonary embolism is classified as acute if it meets any of the following criteria:

• Time Criterion: Symptom onset and physical sign presentation occur immediately after obstruction of pulmonary vessels.
• Embolus Size Criteria:
  • Embolus is located centrally within the vascular lumen.
  • Embolus occludes a vessel.
  • Embolus causes distention of the involved vessel.

Chronic Pulmonary Embolism

A pulmonary embolism is classified as chronic if it meets any of the following criteria:

• Time Criterion: A markedly progressive development of dyspnea over time, generally as a result of pulmonary hypertension.
• Embolus Size Criteria:
  • Embolus is eccentric and contiguous with the vessel wall.
  • Embolus reduces the arterial diameter by ≥ 50%.
  • Evidence of recanalization within the thrombus.
  • Presence of an arterial web.

Classification Based on Disease Severity

In addition to the time of presentation and the size of the embolus, a pulmonary embolism can also be classified based on the severity of disease. Three major classifications exist: massive (5% of cases), submassive ( 40% of cases), and low-risk ( 55% of cases).

Massive Pulmonary Embolism

• 5% of pulmonary emboli
• Sustained hypotension (systolic blood pressure <90 mm Hg) for at least 15 minutes or requiring inotropic support. This is not due to other possible causes of hypotension such as arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction.
• Pulselessness.
• Persistent profound bradycardia (heart rate < 40 bpm with signs or symptoms of shock).

Submassive Pulmonary Embolism

• 40% of pulmonary emboli
• An acute pulmonary embolus without systemic hypotension but with either right ventricular dysfunction or myocardial necrosis.. Myocardial necrosis is defined as either elevation of troponin I (>0.4 ng/mL) or elevation of troponin T (>0.1 ng/mL).

• Submassive pulmonary embolism is associated with:

• A significantly higher rate of in-hospital complications.
• A higher potential for long-term pulmonary hypertension and cardiopulmonary disease.

• Though patients with submassive pulmonary emboli may initially appear hemodynamically and clinically stable, there is potential to undergo a cycle of progressive right ventricular failure. A submassive pulmonary embolism requires continuous monitoring to prevent irreversible damage and death.

Saddle Pulmonary Embolism

• A saddle pulmonary embolism is classified as an embolus that lodges at the bifurcation of the main pulmonary artery into the right and left pulmonary arteries.
• Saddle pulmonary embolisms are typically classified as submassive.

Low-Risk Pulmonary Embolism

• 55% of pulmonary emboli
• An acute pulmonary embolism without the life threatening clinical markers that define massive or submassive pulmonary emboli.

Pathophysiology

The diagram below summarizes the sequence of pathophysiologic events in pulmonary embolism:

Differentiation of Pulmonary Embolism from other Disorders

Pulmonary embolism must be distinguished from other life-threatening causes of chest pain including acute myocardial infarction, aortic dissection, and pericardial tamponade, as well as a large list of non-life-threatening causes of chest discomfort and Shortness of breath.

Overview

Each year in United States, there are between 300,000-600,000 cases of pulmonary embolism (PE). The prevalence of the disease increases as age increases.

Risk Factors

The most common sources of pulmonary emboli are proximal leg deep venous thromboses (DVTs) or pelvic vein thromboses. Any risk factor for DVT also increases the risk of pulmonary embolism, and therefore DVT and PE are considered to be a continuum termed venous thromboembolism (VTE). Approximately 15% of patients with a DVT will develop a pulmonary embolus. Smoking, estrogen-containing hormonal contraceptives, and immobilization (including long distance travel) are common risk factors.

The development of thrombosis is classically due to a group of causes referred to as Virchow's triad. Virchow's triad includes alterations in blood flow, factors in the vessel wall, and factors affecting the properties of the blood. It is common for more than one risk factor to be present.

Figure: Virchow's triad encompasses three broad categories of factors that are thought to contribute to venous thrombosis.

Medical conditions included in the triad are:

• Alterations in blood flow: Alterations in blood flow can be caused by some of the following conditions:
  • Pregnancy which is a pro-coagulant
  • Obesity which is also a pro-coagulant
  • Being immobile for long periods of time. The immobilizations include:
    • After a surgery
    • Injury
    • Long-distance air travel
• Factors in the vessel wall:
  • This is of limited direct relevance in VTE
• Factors affecting the properties of the blood (pro-coagulant state):
  • Estrogen-containing hormonal contraception
  • Genetic thrombophilias which include:
    • Factor V Leiden
    • Prothrombin mutation G20210A
    • Protein C deficiency
    • protein S deficiency
    • Antithrombin deficiency
    • Hyperhomocysteinemia
    • Plasminogen/Fibrinolysis disorders
  • Acquired thrombophilias which include:
    • Antiphospholipid syndrome
    • Nephrotic syndrome
    • Paroxysmal nocturnal hemoglobinuria

Complications

Pulmonary embolism can be acutely complicated by the development of cardiogenic shock, pulseless electrical activity and sudden cardiac death and chronically by the development of pulmonary hypertension. The medical management of pulmonary embolism often requires the administration of potent parenteral anticoagulants and fibrinolytics and massive bleeding can be a complication of their administration. If left untreated almost one-third of patients with pulmonary embolism die, typically from recurrent pulmonary embolism. However, with prompt diagnosis and treatment, the mortality rate is approximately 2–8%. The true mortality associated with pulmonary embolism may be underestimated as two-thirds of all pulmonary embolism cases are diagnosed by autopsy.

Acute Complications

• Heart failure or shock
• Pulmonary hypertension
• Pulseless Electrical Activity
• Sudden cardiac death

Chronic Complications

• Chronic thromboembolic hypertension (rare - 1%)
• Pulmonary hypertension
• Recurrent pulmonary embolism

Complications of Firbrinolytic Therapy for Pulmonary Embolism

• Severe bleeding can occur as a complication of fibrinolytic treatment:

• Major hemorrhage - 10%
• Non major hemorrhage - 20%
• Intracranial hemorrhage - 0.5%

Prognosis

If left untreated, almost one-third of the patients die, typically from recurrent PE. However, with prompt diagnosis and treatment, the mortality rate is approximately 2–8%. Unfortunately, two-thirds of all PE cases are diagnosed by autopsy. Pulmonary embolism causes death in approximately 16% of hospitalized patients.

A 26% mortality rate associated with untreated pulmonary embolism is often cited based upon a trial published in 1960 by Barrit and Jordan which compared anti-coagulation against placebo for the management of pulmonary embolism. Barritt and Jordan performed their study in the Bristol Royal Infirmary in 1957. This study is the only placebo controlled trial ever to examine the efficacy of anticoagulants in the treatment of pulmonary embolism. The results of this were so convincing that the trial has not been repeated. On the other hand, the reported mortality rate of 26% in the placebo group may underestimate the true mortality insofar as the sensitivity and specificity of diagnostic technology in 1957 may have only allowed the detection of massive pulmonary emboli.

Risk Stratification in Assessing Prognosis

The prognosis in a patient with pulmonary embolism depends upon:

• The extent of the pulmonary vasculature that is occluded
• Co-existence of other medical conditions (i.e. the patient's comorbidities)

Clinical correlates of mortality among patients with pulmonary embolism are listed below.

Hemodynamic status

Observational studies such as the International COoperative Pulmonary Embolism Registry (ICOPER) and the Management and Prognosis in Pulmonary Embolism Trial (MAPPET) have shown that shock and hypotension are principal high risk markers of early death in acute PE. The MAPPET study demonstrated that systemic shock was associated with mortality of 24.5% where as hypotension (but not shock) was associated with the mortality of 15.2%.

A post-hoc analysis of the ICOPER study demonstrated that the 90-day all-cause mortality rate was 52.4% (95% CI,43.3–62.1%) among patients with a systolic blood pressure less than 90 mm Hg compared to 14.7% (95% CI, 13.3–16.2%) among patients with a normal blood pressure.

The PESI (Pulmonary Embolism Severity Index) study demonstrated that hypotension (blood pressure <100 mm Hg) is associated with a mortality of nearly 50%.

Markers of Right Ventricular Dysfunction (RVD)

The presence of right ventricular dysfunction (RVD) on echocardiography has been associated with a higher mortality in the setting of pulmonary embolism.

Association of RV Dysfunction (RVD) on Echocardiography With Mortality in Pulmonary Embolism

Study	Year	Patients (n)	Blood pressure	Echocardiographic criteria	RVD(present) vs. RVD(absent): Mortality percentage(%)
Goldhaber et al.	1993	101	Normotensive	RV hypokinesis and dilatation	4.3% vs. 0%
Ribeiro et al.	1997	126	Normotensive and hypotensive	RVD	12.8% vs. 0%
Kasper et al.	1997	317	Normotensive and hypotensive	RV >30 mm or TI >2.8 m/s	13% vs. 0.9%
Grifoni et al.	2000	162	BP ≥ 100 mmHg	Atleast one of the following RV >30 mm or RV/LV >1 Paradox septal systolic motion AcT <90 ms or TIPG >30 mmHg	4.6% vs. 0%
Kucher et al.	2005	1035	BP ≤ 90 mmHg	RVD	16.3% vs. 9.4%

Abbreviations Used: RV , right ventricle; TI, tricuspid insufficiency; LV, left ventricle; AcT, ACceleration Time of right ventricular ejection; TIPG, tricuspid insufficiency peak gradient.

Brain Natriuretic Peptide

In patients with a pulmonary embolism, elevated plasma levels of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic peptide) have been associated with higher mortality. Levels of N-terminal pro-brain natriuretic peptide greater than 500 ng/L serve as an indicator of the burden of PE and are associated with death.

Serum Troponin

Elevated serum troponin levels are associated with an increased risk of death among pulmonary embolism patients. The elevation of troponin in patients with a massive pulmonary embolism does not reflect epicadial coronary artery disease but rather transmural RV infarctions on autopsy.

Hyponatremia

Hyponatremia at the time of presentation is associated with increased mortality and hospital readmission

Electrocardiographic Abnormalities

The electrocardiographic findings in pulmonary embolism can provide prognostic information (click here to read more). EKG findings that are associated with a poor prognosis include:

1. Atrial arrhythmias
2. Right bundle branch block
3. Q-waves in the inferior leads
4. Precordial T-wave inversion and ST-segment changes.
5. Development of a QR wave in lead V₁ is identified as an independent risk factor for an adverse prognosis.

Wells Score

The Wells score is a simple, commonly used clinical risk prediction tool to evaluate the need for further testing in patients suspected to have pulmonary embolism.

Wells Score Calculator for PE

Variable	Wells
Clinically suspected DVT (leg swelling, pain with palpation)	3.0
Alternative diagnosis is less likely than PE	3.0
Immobilization/surgery in previous four weeks	1.5
Previous history of DVT or PE	1.5
Tachycardia (heart rate more than 100 bpm)	1.5
Malignancy (treatment for within 6 months, palliative)	1.0
Hemoptysis	1.0

Wells criteria

• The following scoring system is used to assess the possible risk to a patient. It also shows if there is a need for further testing with D-dimer or CT scan:

• Score >6.0 - High probability (~59%).
• Score 2.0 to 6.0 - Moderate probability (~29%).
• Score <2.0 - Low probability (~15%).

• The modified extended version of the Wells score has been proposed.

• An alternate dichotomous interpretation is:

• Score > 4 - PE likely. Consider diagnostic imaging.
• Score 4 or less - PE unlikely. Consider D-dimer to rule out PE.

• A simplified Wells criteria has been proposed, according to which all the 7 risk variables (table) are assigned 1 point each. A score ≤ 1 is categorized as unlikely to be PE. This score needs further validation in prospective studies.

Symptoms

The symptoms of pulmonary embolism (PE) depends on the severity of the disease. A Pulmonary embolism may be an incidental finding in so far as many patients are asymptomatic. The common symptoms of PE range from mild dyspnea, chest pain, and tachypnea, to sustained hypotension and shock. The absence of these symptoms may be associated with a reduced clinical probability of pulmonary embolism, however it does not exclude the diagnosis of pulmonary embolism. The symptoms of lower extremity deep venous thrombosis may also be present.

Physical Examination

Pulmonary emboli are associated with the presence of tachycardia and tachypnea. Signs of right ventricular failure include jugular venous distension, a right sided S3, and a parasternal lift. These signs are often present in cases of massive pulmonary emboli.

Laboratory Studies

The results of routine laboratory tests including arterial blood gas analysis are non-specific in making the diagnosis of pulmonary embolism. These laboratory studies can be obtained to rule-out other cause of chest discomfort and tachypnea. In patients with acute pulmonary embolism, non-specific lab findings include: leukocytosis, elevated ESR with an elevated serum LDH and serum transaminase (especially AST or SGOT).

Arterial Blood Gas

Hypoxemia, hypocapnia, increased alveolar-arterial gradient, and respiratory alkalosis are common findings that may be observed in patients with pulmonary embolism. In patients with suspected PE, Rodger et al, demonstrated that ABG analysis did not have sufficient negative predictive value, specificity, or likelihood ratios to be considered useful in the management these patients. Similar findings were observed by the PIOPED II investigators.

D-Dimer

D-dimer is a fibrin degradation product. D-dimer levels are elevated in the plasma after the acute formation of a blood clot. The majority of patients with pulmonary embolism have some degree of endogenous fibrinolysis with an elevation in D-dimer levels, therefore there is a high negative predictive value in ruling out a pulmonary embolism when D-dimer levels are low. However a wide range of diseases are associated with mild degree of fibrinolysis which elevate D-dimer levels and contribute towards a reduced specificity and a poor positive predictive value of a high D-dimer level. This means that it is more likely that one can rule out a PE with a low D-dimer level, but cannot necessarily confirm the diagnosis of a PE based on a high D-dimer level. Other disease states that can also have a high d-dimer level include pneumonia, congestive heart failure (CHF), myocardial infarction (MI) and malignancy. False-negative values may occur in patients with prolonged symptoms of venous thromboembolism (≥14 days), patients on therapeutic heparin therapy, and patients with suspected deep venous thrombosis on oral anticoagulation, as these patients have will have low D-dimer levels in the presence of a PE.

Flowchart summarizing the role of D-dimer in the diagnosis of PE

Patients with suspection of Pulmonary embolism

Clinically Low or Moderate

Clinically High

D-Dimer Positive

D-Dimer Negative

No treatment

Further Tests

Further Tests

Electrocardiographic Findings

EKG abnormalities in the setting of pulmonary emolism are non-specific. The EKG may also lack sensitivity as the EKG may be normal in the setting of a pulmonary embolus. In a prospective study EKG abnormalities were present in 70% of patients with documented acute pulmonary embolism. The most common EKG abnormality was nonspecific ST-segment and T-wave changes. An electrocardiogram (ECG) is routinely performed in all patients with chest pain to assess for a myocardial infarction, but the diagnosis of a pulmonary embolism should be kept in mind as well.

Chest X Ray

A chest X ray is often obtained in patients with shortness of breath to diagnose pneumonia, congestive heart failure, and rib fracture. Although the chest X ray in the setting of a pulmonary embolism is often abnormal, the findings are non-specific and are not diagnostic of a pulmonary embolus.

CT Pulmonary Angiography

Recent studies have supported the use of MDCT as the best diagnostic tool in the assessment of pulmonary embolism.

The diagnostic accuracy of CTA, either alone or in conjunction with other laboratory findings is as follows:

• Sensitivity - 91 %
• Specificity - 96 %

V/Q Scanning

The utilization of V/Q scanning has declined since the advent of more widespread availability of CT technology, however it may be useful in particular subgroups of patients, such as:

1. Patients who have a known allergy to iodinated contrast. To read more about contrast allergy, click here.
2. In pregnant patients to minimize exposure to radiation.
3. For patients who are in a hospital lacking CT technology.

The following table summarizes the possible outcomes of a V/Q scan:

V/Q Scan	Clinical Probability	Diagnosis
Normal	any probability	PE excluded
Low probability scan	Low	PE excluded
High probability scan	High	PE confirmed
Variable result/Non-diagnostic	Variable	Serial lower extremity USG or pulmonary angiography

Echocardiography

Approximately 40% of patients with pulmonary embolism have evidence of right heart strain on echocardiography. When RV dysfunction or RV thrombus are identified on echocardiography, this finding provides further risk stratification. Routine echocardiography in patients with suspected pulmonary embolism is not required. However if elevations in the cardiac troponins or brain natriuretic peptide are present, then acute right ventricular strain may be present and echocardiography may be warranted.

MRI

Magnetic resonance pulmonary angiography should be considered in the setting of a pulmonary embolism only at centers that routinely perform it well and only for patients for whom standard tests are contraindicated. MRA has a sensitivity and specificity of 78% and 99% respectively.

Prompt recognition, diagnosi and treatment of pulmonary embolism is criticl. Anticoagulant therapy is the mainstay of treatment for patients who are hemodynamically stable. If hemodynamic compromise is present, then fibrinolytic therapy is recommended.

Step 1: Establish The Diagnosis Of Pulmonary Embolism

In hospitals that have experience in performing and interpreting CT pulmonary angiography, the following flowchart approach can be adopted.

Determine chances of PE

Low chance

High chance

D-dimer

<500 ng/ml

>500 ng/ml

CT Pulmonary angiography

PE excluded

Negative

Positive

PE excluded

PE confirmed

Note: If there is a high clinical suspicion of pulmonary embolism, then anticoagulation can begin with a parenteral agent such as unfractionated heparin during the process of performing the diagnostic studies.

Step 2: Use A Risk-Stratified Approach to Treat the Patient with Pulmonary Embolism

Confirmed PE

Assess Clinical Stability

Unstable

Stable

Blood Pressure =< 90mm Drop >=40mm for > 15 min

Assess RV function Biomarkers of injury

Thrombolysis Catheter embolectomy Surgery

No Dysfunction No Injury

Dysfunction No Injury

Dysfunction + Injury

Anticoagulate Early Discharge

Anticoagulate Ward admit

ICU/Thrombolytics

Low Risk Pulmonary Embolism

Low-risk PE: Therapeutic anticoagulation, unless contraindicated.

Sub Massive Pulmonary Embolism

Submassive PE: If the patient is hemodynamically stable without major RV dysfunction or infarction, therapeutic anticoagulation should be started. In some cases, thrombolysis may be indicated.

Massive Pulmonary Embolism

Massive PE: Thrombolysis is indicated and ICU admission may be required. Initial supportive therapies for these patients may include:

• Respiratory support with oxygen for hypoxemic patients and mechanical ventilation in cases of severe hypoxemia or pending respiratory failure.
• Hemodynamic support with intravenous fluids or intravenous vasopressors is indicated for hypotensive patients. Intravenous fluids should be administered with caution as increased right ventricular load can disable the oxygen balance.
• If anticoagulation is contraindicated, then an IVC filter is recommended.

Step 3: Assess Treatment Response and Need for Device Based Therapy

Acute PE confirmed

Anticoagulation contraindicated ?

Yes

No

IVC filter

Risk Stratification

Low-risk PE

Submassive PE

Massive PE

Anticoagulation

Anticoagulation

Assess clinically for evidence of increased severity

Evidence of Shock (SBP <90 mmHg) or respiratory failure

Is Thrombolytic Contraindicated?

Yes

No

Surgical emblectomy or catheter based interventions

Hold Anticoagulation, Give Thrombolytics then resume Anticoagulations

Patient shows clinical improvement

No

Yes

Surgical emblectomy or catheter based interventions

Continue anticoagulation

Acute Therapies

Anticoagulation

The most common cause of mortality in patients with a pulmonary embolism, is a recurrent PE occurring within a few hours of the initial event. Anticoagulation prevents further clot formation and extension, therefore it should be started as early as possible. Anticoagulation does not disaggregate existing clot, but it does facilitate the action of the body's endogenous lytic system. Anticoagulation is the cornerstone of therapy in an acute pulmonary embolism. After initial risk stratification. Certain conditions like pericardial tamponade and aortic dissection can mimic pulmonary embolism. The use of anticoagulants is contraindicated in these medical conditions. Proceed with caution if these conditions are high on the differential. Immediate treatment should be initiated based on the following guidelines:

• Initial treatment with parenteral anticoagulants, including subcutaneous low molecular weight heparin (such as enoxaparin and dalteparin), subcutaneous fondaparinux, or intravenous unfractionated heparin, should be administered unless contraindicated.
• ACCP guidelines recommend low molecular weight heparin or fondaparinux instead of intravenous unfractionated heparin.
• If there is moderate-to-high clinical suspicion of a PE, anticoagulation should be initiated while awaiting confirmatory tests.
• Vitamin K antagonists such as warfarin should be started the same day. Parenteral anticoagulation should be continued for at least 5 days, and preferably until INR is 2.0 or above for 1-2 days.
• Warfarin therapy often requires frequent dose adjustment and monitoring of the INR. In PE, the INR goal should be between 2.0 and 3.0.
• In patients with suspected or confirmed heparin-induced thrombocytopenia, lepirudin or argatroban should be used.

Thrombolysis

• Unless previously contraindicated, thrombolysis is indicated in patients with a massive PE or those with a submassive PE who develop or are at risk of developing hypotension (SBP < 90 mmHg).
• Administration of a fibrinolytic via a peripheral intravenous catheter is recommended.
• FDA recommends a 100 mg dose of alteplase administered as a continuous infusion over 2 hours. This treatment is supported by AHA and ACCP guidelines.
• Withhold anticoagulation during the 2 hours of fibrinolytic infusion.
• The role of thrombolysis in a submassive PE is not established at this point. Two ongoing trials are investigating the efficacy and safety of this approach.
• No large clinical trial has demonstrated a mortality benefit of thrombolytic therapy. However, it helps by accelerating clot lysis, improving pulmonary perfusion, and improving right ventricular function.

To read more about dosage, contraindications, and guidelines, click here.

Surgical procedures

• Catheter-assisted thrombus removal is recommended in patients with a massive PE who have contraindications to thrombolytic therapy or have failed thrombolysis.
• Thrombectomy is also recommended for patients who are in severe shock that may cause the patient to die before thrombolysis takes effect (hours).
• Pulmonary embolectomy is also recommended if a patient with the above conditions fails catheter-assisted embolectomy.

IVC filter

• An IVC filter is indicated for patients for whom anticoagulation is contraindicated.
• Anticoagulation should be restarted once the contraindication is resolved.

Chronic Therapies

• After treatment in the hospital, the patient should continue anticoagulation treatment for 3 months if the PE is provoked by surgery or a nonsurgical transient risk factor.
• An abnormal D-dimer level at the end of the treatment course might signal the need for continued treatment with anticoagulation for a first time unprovoked pulmonary embolus.
• Long-term treatment is usually recommended with vitamin K antagonists like warfarin, unless contraindicated or some special circumstances.
• The recommended therapeutic INR range for patients with PE is 2.0-3.0.
• Continued warfarin administration needs close monitoring. The patient should have an appointment with the "anticoagulation clinic" before leaving the hospital.

Extended anticoagulation

Extended treatment means extending the anticoagulation therapy beyond the first 3 months. It is recommended in the following scenarios:

• For a pulmonary embolism that is unprovoked. The patient's risk should be re-evaluated at 3 months to consider whether or not extended therapy is warranted.
• Active cancer.
• Recurrent venous thromboembolism.
• Chronic thrombembolic pulmonary hypertension.

Salient features:

• For extended therapy, the continued need for anticoagulation and the risk-benefit ratio should be re-evaluated at periodic intervals (eg, annually).
• Patients with recurrent thromboembolic disease, with or without anticoagulation, should be evaluated for possible thrombophilias.

Specific circumstances

• Malignancy: Low molecular weight heparin is favored over warfarin based on the results of the CLOT trial.
• Pregnancy: Low molecular weight heparin is preferred to avoid the known teratogenic effects of warfarin.
• Asymptomatic patients who are diagnosed with an incidental PE should be managed with the same criteria as those with symptomatic PE.

Newer anticoagulants

• Dabigatran (direct thrombin inhibitor), Rivaroxaban (Factor Xa inhibitor), and other drugs in the same classes, provide an alternate option to warfarin/LMWH for treatment of PE.
• Advantages include the availability of an oral formulation, no frequent monitoring requirement, a predictable effect profile, and few (known) drug interactions.
• Disadvantages include the currently limited prospective trial data, the theoretical interaction with statins (as they are metabolized by the same CYP3A4 enzyme), and the risk of bleeding.