Pulmonary embolism treatment approach

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

Overview

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

Treatment Algorithm

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.

Clinical assessment for pulmonary embolism ❑ Clinically suspected DVT (leg swelling, pain with palpation): award 3 points ❑ Alternative diagnosis is less likely than PE: award 3 points ❑ Immobilization/surgery in previous four weeks: award 1.5 points ❑ Previous history of DVT or PE: award 1.5 points ❑ Tachycardia (heart rate more than 100 bpm): award 1.5 points ❑ Hemoptysis: award 1 point ❑ Malignancy (treatment for within 6 months, palliative): award 1 point Interpretation Wells criteria Score: >6.0 - High probability of PE 2.0 to 6.0 - Moderate probability of PE <2.0 - Low probability of PE Wells score calculator Interpretation Modified Wells criteria >4.0 - PE likely ≤4.0 - PE unlikely

High probability. ❑ Consider imaging of the pulmonary arteries

Moderate probability ❑ Consider checking D-dimer

Low probability ❑ Consider checking D-dimer

Perform the following investigations ❑ D-dimer ❑ Erythrocyte agglutination assay (takes upto 2 min) ❑ Semi-quantitative latex agglutination assay (takes upto 5 min) ❑ Semi-quantitative rapid ELISA (takes upto 10 min) ❑ Qualitative rapid ELISA (takes upto 10 min) ❑ Quantitative latex agglutination assay (takes upto 15 min) ❑ Quantitative rapid ELISA (takes upto 30 min) ❑ V/Q scan

PERC(pulmonary embolism rule out criteria) rule If the patient is presenting with dyspnea, and chest pain in the emergency department, fulfill the following criteria, it excludes PE in the patients with a low clinical suspicion for thromboembolism. ❑ Age <50 years ❑ Tachycardia ❑ Hemoglobin saturation above 95 % ❑ Absent history of hemoptysis ❑ Absent history of estrogen use ❑ Absent history of DVT or PE ❑ Absent history of unilateral leg swelling ❑ Absent history of surgery/trauma requiring hospitalization within the prior four weeks PERC rule has low positive predictive value and specificity

PE confirmed if ❑ High clinical probability with high-probability V/Q scan has 95% chance of having PE.

PE can not be excluded ❑ D-dimer level >500 ng/mL

PE excluded ❑ Normal V/Q scan ❑ Low clinical probability with low-probability V/Q scan has 4% chance of having PE ❑ D-dimer level <500 ng/mL excludes the diagnosis in low pretest probability

Perform CT Pulmonary angiography OR Pulmonary angiography to confirm the diagnosis of PE ❑ Pulmonary angiography Contraindicated in renal insufficiency and contrast allergy. ❑ Pulmonary angiography is the "gold standard" in the diagnosis of acute PE. ❑ Embolus is visulized as a filling defect or abrupt cutoff of a small vessel. ❑ Complications includes contrast reactions, cardiac arrhythmia, respiratory insufficiency and those related to the catheter insertion. ❑ CT Pulmonary angiography Contraindicated in renal insufficiency and contrast allergy. ❑ It can help to diagnose alternative diagnosis which can explain the patient's symptoms and signs. ❑ It is relative quicker procedure to administer.

Consider alternative diagnosis

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.

2008 ESC Guidelines Treatment High-risk Pulmonary Embolism (DO NOT EDIT)

Class I

"1. Anticoagulation with unfractionated heparin should be initiated without delay in patients with high-risk PE. (Level of Evidence: A) "

"2. Systemic hypotension should be corrected to prevent progression of RV failure and death due to PE. (Level of Evidence: C)"

"3. Vasopressive drugs are recommended for hypotensive patients with PE. (Level of Evidence: C)"

"4. Oxygen should be administered in patients with hypoxaemia.(Level of Evidence: C)"

"5. Thrombolytic therapy should be used in patients with high-risk PE presenting with cardiogenic shock and/or persistent arterial hypotension.(Level of Evidence: A)"

"6. Surgical pulmonary embolectomy is a recommended therapeutic alternative in patients with high-risk PE in whom thrombolysis is absolutely contraindicated or has failed.(Level of Evidence: C)"

Class III

"1. Aggressive fluid challenge is not recommended. (Level of Evidence: B)"

Class IIa

"1. Dobutamine and dopamine may be used in patients with PE, low cardiac output and normal blood pressure. (Level of Evidence: B)"

Class IIb

"1.Catheter embolectomy or fragmentation of proximal pulmonary arterial clots may be considered as an alternative to surgical treatment in high-risk patients when thrombolysis is absolutely contraindicated or has failed. (Level of Evidence: C)"

2008 ESC Guidelines Treatment Non-high-risk Pulmonary Embolism (DO NOT EDIT)

Class I

"1. Anticoagulation should be initiated without delay in patients with high or intermediate clinical probability of PE while diagnostic workup is still ongoing. (Level of Evidence: C)"

"2. Use of LMWH or fondaparinux is the recommended form of initial treatment for most patients with non-high-risk PE. (Level of Evidence: A) "

"3. In patients at high risk of bleeding and in those with severe renal dysfunction, unfractionated heparin with an aPTT target range of 1.5–2.5 times normal is a recommended form of initial treatment. (Level of Evidence: C) "

"4. Initial treatment with unfractionated heparin, LMWH or fondaparinux should be continued for at least 5 days and (Level of Evidence: A) may be replaced by vitamin K antagonists only after achieving target INR levels for at least 2 consecutive days (Level of Evidence: C)"

Class III

"1. Thrombolytic therapy should be not used in patients with low-risk PE (Level of Evidence: B) "

Class IIb

"1. Routine use of thrombolysis in non–high-risk PE patients is not recommended, but it may be considered in selected patients with intermediate-risk PE (Level of Evidence: B) "

ESC 2008 Guidelines Recommendations Long-term treatment (DO NOT EDIT)

Class I

"1. For patients with PE secondary to a transient (reversible) risk factor, treatment with a VKA is recommended for 3 months.(Level of Evidence: A)"

"2. For patients with unprovoked PE, treatment with a VKA is recommended for at least 3 months. (Level of Evidence: A)"

"3. For patients with a second episode of unprovoked PE, long-term treatment is recommended. (Level of Evidence: A)"

"4. In patients who receive long-term anticoagulant treatment, the risk/benefit ratio of continuing such treatment should be reassessed at regular intervals. (Level of Evidence: C)"

"5. In patients with PE, the dose of VKA should be adjusted to maintain a target INR of 2.5 (range 2.0–3.0) regardless of treatment duration.(Level of Evidence: A)"

Class IIb

"1. Patients with a first episode of unprovoked PE and low risk of bleeding, and in whom stable anticoagulation can be achieved, may be considered for long-term oral anticoagulation. (Level of Evidence: B)"

Class IIa

"1. For patients with PE and cancer, LMWH should be considered for the first 3–6 months (Level of Evidence: B) after this period, anticoagulant therapy with VKA or LMWH should be continued indefinitely or until the cancer is considered cured.(Class I,Level of Evidence: C)"