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.; Rim Halaby, M.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.

Step 1: Confirm PE

Shown below is an algorithm depicting the initial diagnostic approach to pulmonary embolism.

Does the patient who is suspected to have PE have hypotension or shock?

Yes

No

Suspected high-risk PE

Suspected non-high risk PE

Administer anticoagulation (in case there are no contraindications) during the diagnostic workup

Is a CT available immediately?

What is the pretest probability of PE? Assess the pretest probability of PE by using one of the risk score: - Wells score - Geneva score - PERC

No

Yes

Order echocardiography

Does the patient have RV overload?

Low pretest probability

Intermediate pretest probability

High pretest probability OR PE is likely

Administer anticoagulation (in case there are no contraindications) during the diagnostic workup

Administer anticoagulation (in case there are no contraindications) during the diagnostic workup

No

Yes

Order CT

Order D-dimer

Positive

Negative

Positive

Negative

Is the patient unstable OR no other tests are available?

Is the patient stabilized AND CT is now available?

Order CT

PE is excluded

Order CT

Positive

Negative

Positive

Negative

PE is excluded

Consider thrombolytic therapy or embolectomy

Order CT

PE is confirmed

PE is excluded

PE is confirmed

PE is excluded

PE is confirmed

PE is excluded

Positive for PE

Negative for PE

PE is confirmed

PE is excluded

Step 2: Initial Treatment

Shown below is an algorithm depicting the initial management of pulmonary embolism.

Assess the severity of pulmonary embolism

Massive PE (also known as high-risk PE) Cardiogenic shock OR Persistent hypotension (≤90mmHg) OR Drop of the blood pressure by ≥ 40mmHg for > 15 min OR Pulselessness OR Profound bradycardia (<40 bpm) with findings of shock

Submassive PE (also know as intermediate-risk PE) Right ventricular dysfunction AND/OR Myocardial injury (Troponin +)

Low-risk PE No cardiogenic shock AND No hypotension AND No right ventricular dysfunction AND No myocardial injury (Troponin -)

Provide hemodynamic and respiratory support Begin high dose unfractionated heparin : Bolus 10.000 U Continuous infusion of at least 1250 U/hour for a targeted apTT of at least 80 s Administer rapidly 500-1000 mL of normal saline (Caution with fluid overload) Have a low threshold for ionotropes (dopamine or dobutamine) Administer oxygen for hypoxemic patients

Is there any contraindication for fibrinolytic therapy?

Is there any contraindication for anticoagulation therapy?

Is there any contraindication for anticoagulation therapy?

NO

YES

NO

YES

NO

YES

Discontinue unfractionated heparin AND Begin fibrinolytic therapy

Surgical pulmonary embolectomy OR Percutaneous catheter embolectomy

Anticoagulation therapy AND Hospital admission

IVC filter AND Hospital admission

Anticoagulation therapy AND Early discharge/home treatment

IVC filter AND Early discharge/home treatment

Does the patient fail to improve OR Develop cardiogenic shock? OR Develop hypotension?

Does the patient fail to improve OR Develop cardiogenic shock? OR Develop hypotension (<90 mmHg)? OR Develop respiratory distress (SaO2<95% with Borg score>8 or altered mental status) OR Have moderate to severe RV dysfunction (RV hypokinesis or estimated RVSP>40 mmHg) OR Elevated biomarkers (troponin> upper limit of normal, BNP>100 pg/mL, or pro-BNP>900 pg/mL)

YES

NO

YES

NO

Surgical pulmonary embolectomy OR Percutaneous catheter embolectomy

Continue with the same treatment

Is there any contraindication for fibrinolytic therapy?

Continue with the same treatment

NO

YES

Hold anticoagulation and give thrombolytics

Surgical pulmonary embolectomy OR Percutaneous catheter embolectomy

Does the patient fail to improve?

YES

NO

Surgical pulmonary embolectomy OR Percutaneous catheter embolectomy

Continue with the same treatment

Anticoagulation Therapy

Initial Anticoagulation Therapy

Begin initial anticoagulation therapy in: ❑ Confirmed PE OR ❑ High or intermediate probability of PE while awaiting the diagnostic tests

Is the patient high risk or non-high risk?

High risk

Non-high risk

❑ Administer IV unfractionated heparin

Does the patient have: ❑ High risk of bleeding OR ❑ Severe renal failure?

Yes

No

❑ Administer unfractionated heparin: ❑ IV injection OR ❑ SC injection

❑ Administer ONE of the following: ❑ SC low molecular weight heparin (1st line) ❑ SC fondaparinux (1st line) ❑ IV unfractionated heparin ❑ SC unfractionated heparin

Long Term Anticoagulation Therapy

The long term management of PE depends on whether the episode is the first one or not, whether it is provoked or unprovoked, and on the risk of bleeding of the patient. Among non cancer patients, the first line therapy for long term management of PE is vitamin K antagonists (VKA); whereas the first line treatment among cancer patients is low molecular weight heparin. If long term treatment with VKA is decided, VKA should be started at the same day with heparin allowing for at least 5 days of overlap until the INR is ≥2 for at least 24 hours. Among patients on extended anticoagulation therapy, the risk vs benefits of the anticoagulation therapy should be assessed regularly (for example annually).

Is this the first episode of PE?

YES

NO

Is PE provoked?

What is the risk of bleeding?

Yes, transient reversible risk factor

Yes, cancer

No (unprovoked)

Low or moderate

High

Therapy for 3 months ❑ VKA (first line) OR ❑ LMWH OR ❑ Dabigatran OR ❑ Rivaroxaban

Extended therapy or until cancer is cured ❑ LMWH (first line) OR ❑ VKA OR ❑ Dabigatran OR ❑ Rivaroxaban

Therapy for ≥ 3 months ❑ VKA (first line) OR ❑ LMWH OR ❑ Dabigatran OR ❑ Rivaroxaban

Extended therapy ❑ VKA (first line) OR ❑ LMWH OR ❑ Dabigatran OR ❑ Rivaroxaban

Therapy for 3 months ❑ VKA (first line) OR ❑ LMWH OR ❑ Dabigatran OR ❑ Rivaroxaban

Re-assess the risk of bleeding

Low or moderate

High

Extended therapy

Do not extend the therapy beyond the initial 3 months

Note that edoxaban has been evaluated for the treatment of VTE and is currently seeking approval for this indication.

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.

Step 3: Long Term Treatment

• 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.