Pulmonary embolism medical therapy

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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]; Rim Halaby, M.D. [3]

Overview

Medical therapy for pulmonary embolism (PE) includes anticoagulation therapy and fibrinolytic therapy. Parenteral anticoagulation therapy with either unfractionated heparin, low molecular weight heparin (LMWH), or fondaparinux is indicated in the initial treatment of patients with PE who do not have any contraindications for anticoagulation. Initial parenteral anticoagulation therapy should be started before the completion of the diagnostic workup among patients who have a high pretest probability of PE as well as among those with intermediate pretest probability of PE and an expected delay in the diagnostic results of more than 4 hours. Thrombolytic therapy is indicated for the treatment of massive PE, also known as high-risk PE. Patients with PE require long term anticoagulation therapy with agents such as vitamin K antagonists, LMWH, dabigatran, or rivaroxaban.

Medical Therapy

Initial 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 VKA as an overlap anticoagulation if VKA is planned for long term treatment

❑ Administer ONE of the following: ❑ SC low molecular weight heparin (1st line) ❑ SC fondaparinux (1st line) ❑ IV unfractionated heparin ❑ SC unfractionated heparin ❑ Administer VKA as an overlap anticoagulation if VKA is planned for long term treatment

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.

Parenteral Anticoagulation Therapy

Heparin

• Heparin binds to antithrombin and inactivates thrombin, factors IIa, Xa, IXa, XIa and XIIa; binds to heparin cofactor II and inactivates factor IIa; and binds to factor IXa and inhibits factor X activation.

• The side effects of heparin include bleeding, heparin-induced thrombocytopenia and osteoporosis.

• The anticoagulant effects of heparin can be reversed with IV protamine sulfate.

Heparin Dosage

Shown below is a table depicting the dosage of heparin for the treatment of pulmonary embolism. Note that the dose of heparin used in the treatment of acute coronary syndrome is lower than that used for the treatment of PE.

Mode of administration of Heparin	Dosage
IV injection	80 U/kg as bolus, followed by 18 U/kg/h, OR 70 U/kg as bolus, followed by 15 U/kg/h for stroke or cardiac patients
SC injection	333 U/kg as bolus, followed by 250 U/kg

Adjustment of Heparin Dosage According to aPTT

aPTT should be monitored during treatment with Heparin. Prolongation of apTT correlates with an elevated serum concentration of heparin and requires adjustment of the dosage. Shown below is a table depicting the variation in the dosage according the aPTT.

aPTT	Variation in the dosage
< 1.2 x control (<35 s)	Bolus: 80 U/kg Infusion rate: increase by 4 U/kg/h
1.2-1.5 x control (35-45 s)	Bolus: 40 U/kg Infusion rate: increase by 2 U/kg/h
1.5-2.3 x control (46-70 s)	Continue the same dosage
2.3-3.0 x control (71-90 s)	Infusion rate: decrease by 2 U/kg/h
> 3.0 x control (>90s)	Stop infusion for a period of 1 hour, then Infusion rate: decrease by 3 U/kg/h

Platelet Monitoring

Among patients started on heparin, if the risk of heparin induced thrombocytopenia is more than 1%, monitor platelet count every 2 to 3 days from the 4th until the 14th day of treatment or until the discontinuation of heparin.

Low Molecular Weight Heparin

• LMWH is used as a first line therapy for the initial anticoagulation therapy for PE among patients with non-high risk PE.

• In addition, LMWH can also be used for the long term anticoagulation treatment for PE, but vitamin K antagonist are recommended are first line therapy. However, among cancer patients with provoked PE, LMWH is the first line therapy for the long term anticoagulation treatment.

• LMWH is administered subcutaneously and does not require monitoring for anti X-a or platelets.

• The recommended doses for treatment of PE are:
  • Enoxaparin : 1 mg/Kg body weight (twice daily) OR 1.5 mg/kg once daily
  • Tinzaparin : 175 U/Kg body weight (once daily)

Fondaparinux

• Fondaparinux is used as a first line therapy for the initial anticoagulation therapy for PE among patients with non-high risk PE. Fondaparinux binds to antithrombin and inhibits factor Xa. Fondaparinux does not require monitoring.

• In patients with moderate renal insufficiency (creatinine clearance of 30-50 mL/min), the dose should be reduced by 50%. In cases of renal failure with Cr clearance < 30, it should be avoided.

• Recommended doses for the treatment of PE depend on the weight of the patient:
  • Weight <50 Kg: 5 mg (once daily)
  • Weight between 50 Kg to 100 Kg: 7.5 mg (once daily)
  • Weight >100 Kg: 10 mg (once daily)

Oral Anticoagulation Therapy

Vitamin K Antagonist

• Vitamin K antagonist is the first line therapy for long term anticoagulation treatment of pulmonary embolism, with the exception of patients with cancer among whom LMWH is preferred over warfarin.

• Warfarin should not be administered in pregnancy and LMWH should be use instead.

• Warfarin should be started as soon as possible following the initiation of parenteral anticoagulation therapy, preferably at the same day. Parenteral anticoagulation therapy should be continued for at least 5 days concomitantly with warfarin until INR reaches 2.

• Warfarin is administered as follows:
  • Begin with 5 mg warfarin for 2 days followed by dosing based on the INR.
  • Target INR is 2-3.
  • Monitor INR monthly.
  • If the INR is stable but there is one value 0.5 below or above the target range, continue the same dose and repeat INR within 1-2 weeks.
• NSAIDs, COX2 selective NSAIDs and some antibiotics should be avoided when warfarin is administered.

Factor X Inhibitors

Rivaroxaban is an oral factor X inhibitors that can be used in the long term treatment of PE.

Direct Thrombin Inhibitors

Dabigatran is an oral direct thrombin inhibitors that can be used in the long term treatment of PE.

Thrombolysis

Thrombolysis, also known as clot busting, is the breakdown of blood clots by pharmacological agents. Thrombolytic agents activate the enzyme plasminogen into plasmin which is responsible for the breakdown of fibrin. The thrombolytic agents that are FDA approved are: streptokinase, urokinase, and alteplase.

Indications

• Thrombolytic therapy is indicated for the treatment of massive PE, also known as high-risk PE.

• Thrombolytic therapy is currently not indicated for the treatment of submassive PE, also known as intermediate-risk PE. Patients with intermediate-risk PE have evidence of right ventricular dysfunction or myocardial necrosis in the absence of hypotension. According to the The Pulmonary Embolism Thrombolysis (PEITHO) trial, fibrinolytic therapy in intermediate-risk PE decreased the rate of the compensation of the hemodynamic status at an expense of an elevated rate of major hemorrhage and stroke. A recent metaanalysis of 16 randomized clinical trials of 2115 PE patients, 70.87% of whom are intermediate-risk patients, revealed that thrombolytic therapy in PE is associated with a decreased rate of mortality and an increase rate of major bleed and intracranial hemorrhage, particularly among patients who are older than 65 years.

• When patients initially classified as intermediate-risk fail to improve, or develop cardiogenic shock, hypotension (<90 mmHg), or respiratory distress (SaO2<95% with Borg score>8 or altered mental status), they should be administered fibrinolytic therapy.

Dosage

Shown below is the dosage schedule for the thrombolytic agents:

• Streptokinase (FDA-approved)
  • Loading dose: 250 000 IU over 30 min
  • Maintenance dose: 100 000 IU/h over 12–24 hr
  • Accelerated regimen: 1.5 million IU over 2 hr
• Urokinase (FDA-approved)
  • Loading dose: 4400 IU/kg over 10 min
  • Maintenance dose: 4400 IU/kg/h over 12–24 hr
  • Accelerated regimen: 3 million IU over 2 hr
• Recombinant tissue plasminogen activator (rtPA)
  • Alteplase (FDA-approved): 10-mg IV bolus followed by 90 mg IV infusion over 2 hours
  • Reteplase: 10-U IV bolus followed in 30 mins by another 10-U IV bolus
  • Tenecteplase: 0.5-mg/kg IV bolus (max 50mg)

Administration

• When indicated, fibrinolytic therapy should be administered for a short infusion time (for 2 hours) rather than over prolonged perfusion (for 24 hours).

• In addition, fibrinolytic therapy should be administered via a peripheral vein rather than pulmonary artery catheter.

• Anticoagulation therapy should be withheld during the 2 hours of fibrinolytic infusion.

Contraindications

Shown below is a table summarizing the absolute and relative contraindications to fibrinolytic therapy among pulmonary embolism patients.

Absolute contraindications	Relative contraindications
❑ Previous hemorrhagic stroke or stroke of unknown origin ❑ Ischemic stroke within the last 6 months ❑ Central nervous system tumor or damage ❑ Major trauma, head injury, or surgery within the last 3 weeks ❑ Gastrointestinal bleed within the last month ❑ Known bleeding	❑ Transient ischemic attack within the last 6 months ❑ Oral anticoagulant therapy intake ❑ Advanced liver disease ❑ Infective endocarditis ❑ Peptic ulcer disease that is currently active ❑ Pregnancy or within 1 week post partum ❑ Punctures that are non-compressible ❑ Traumatic resuscitation ❑ Systolic blood pressure >180 mmHg refractory to treatment

Complications of Thrombolytic Therapy

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

2012 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis (DO NOT EDIT)

Recommendations for Initial Treatment of Acute PE

Class I

"1. In patients with acute PE, we recommend initial treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) over no such initial treatment. (Level of Evidence: B)"

"2. In patients with acute PE, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the INR is 2.0 or above for at least 24 h. (Level of Evidence: B)"

"3. In patients with acute PE who are treated with anticoagulants, we recommend against the use of an IVC filter. (Level of Evidence: B)"

"4. In patients with acute PE and contraindication to anticoagulation, we recommend the use of an IVC filter. (Level of Evidence: B)"

"5. In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy. (Level of Evidence: C)"

Class IIa

"1. In patients with low-risk PE and whose home circumstances are adequate, we suggest early discharge over standard discharge (eg,after the first 5 days of treatment). (Level of Evidence: B)"

"2. In patients with acute PE and an IVC filter inserted as an alternative to anticoagulation, we suggest a conventional course of anticoagulant therapy if their risk of bleeding resolves. (Level of Evidence: B)"

"3. In patients with a high clinical suspicion of acute PE, we suggest treatment with parenteral anticoagulants compared with no treatment while awaiting the results of diagnostic tests. (Level of Evidence: C)"

"4. In patients with an intermediate clinical suspicion of acute PE, we suggest treatment with parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected to be delayed for more than 4 h. (Level of Evidence: C)"

"5. In patients with a low clinical suspicion of acute PE, we suggest not treating with parenteral anticoagulants while awaiting the results of diagnostic tests provided that test results are expected within 24 h. (Level of Evidence: C)"

"6. In patients with acute PE, we suggest LMWH or fondaparinux over IV UFH (Level of Evidence: C for LMWH); Level of Evidence: B for fondaparinux) , and over SC UFH (Level of Evidence: B for LMWH; Level of Evidence: C for fondaparinux)."

"7. In patients with acute PE treated with LMWH, we suggest once- over twice-daily administration. (Level of Evidence: C)"

"8. In patients with acute PE associated with hypotension (eg, systolic BP , 90 mm Hg) who do not have a high risk of bleeding, we suggest systemically administered thrombolytic therapy over no such therapy. (Level of Evidence: C)"

"9. In selected patients with acute PE not associated with hypotension and with a low risk of bleeding whose initial clinical presentation or clinical course after starting anticoagulant therapy suggests a high risk of developing hypotension, we suggest administration of thrombolytic therapy. (Level of Evidence: C)"

"10. In patients with acute PE, when a thrombolytic agent is used, we suggest short infusion times (eg, a 2-h infusion) over prolonged infusion times (eg, a 24-h infusion). (Level of Evidence: C)"

"11. In patients with acute PE, when a thrombolytic agent is used, we suggest administration through a peripheral vein over a pulmonary artery catheter. (Level of Evidence: C)"

"12. In patients with acute PE associated with hypotension and who have (i) contraindications to thrombolysis, (ii) failed thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are available, we suggest catheter-assisted thrombus removal over no such intervention. (Level of Evidence: C)"

"13. In patients with acute PE associated with hypotension, we suggest surgical pulmonary embolectomy over no such intervention if they have (i) contraindications to thrombolysis, (ii) failed thrombolysis or catheter-assisted embolectomy, or (iii) shock that is likely to cause death before thrombolysis can take effect (e.g., within hours), provided surgical expertise and resources are available. (Level of Evidence: C)"

2012 ACCP Guidelines - Recommendations for Long-term Treatment of PE (DO NOT EDIT)

Class I

"1. In patients with PE provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period, (ii) treatment of a longer time limited period (eg, 6 or 12 months), or (iii) extended therapy (regardless of bleeding risk). (Level of Evidence: B)"

"2. In patients with PE provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period, (ii) treatment of a longer time-limited period (eg, 6 or 12 months), and (iii) extended therapy if there is a high bleeding risk(Level of Evidence: B). We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Class II, Level of Evidence B)."

"3. In patients with an unprovoked PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration. After 3 months of treatment, patients with unprovoked PE should be evaluated for the risk-benefit ratio of extended therapy. (Level of Evidence: B)"

"4. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (Level of Evidence: B), and we suggest extended anticoagulant therapy in those with a moderate bleeding risk (Class II, Level of Evidence B)."

"5. In patients with a first VTE that is an unprovoked PE and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy. (Level of Evidence: B)"

"6. In patients with PE who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR < 2.0) or higher (INR 3.0-5.0) range for all treatment durations. (Level of Evidence: B)"

"7. In patients with PE and active cancer, if there is a low or moderate bleeding risk, we recommend extended anticoagulant therapy over 3 months of therapy (Level of Evidence: B), and if there is a high bleeding risk, we suggest extended anticoagulant therapy (Class II, Level of Evidence B)."

Class II

"1. In patients with a first VTE that is an unprovoked PE and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy. (Level of Evidence: B)"

"2. In patients with a second unprovoked VTE who have a high bleeding risk, we suggest 3 months of therapy over extended therapy. (Level of Evidence: B)"

"3. In patients with PE and no cancer, we suggest VKA therapy over LMWH for long-term therapy. For patients with PE and no cancer who are not treated with VKA therapy, we suggest LMWH over dabigatran or rivaroxaban for long-term therapy. (Level of Evidence: C)"

"4. In patients with PE and cancer, we suggest LMWH over VKA therapy (Level of Evidence: B). In patients with PE and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy. (Level of Evidence: C)"

"5. In patients with PE who receive extended therapy, we suggest treatment with the same anticoagulant chosen for the first 3 months. (Level of Evidence: C)"

"6. In patients who are incidentally found to have asymptomatic PE, we suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic PE. (Level of Evidence: B)"

2012 ACCP Guidelines - Recommendations for Anticoagulation in Chronic Thromboembolic Pulmonary Hypertenion (DO NOT EDIT)

Class I

"1. In patients with chronic thromboembolic pulmonary hypertension, we recommend extended anticoagulation over stopping therapy. (Level of Evidence: B)"

Class II

"1. In selected patients with chronic thromboembolic pulmonary hypertension, such as those with central disease under the care of an experienced throm boendarterectomy team, we suggest pulmonary thromboendarterectomy over no pulmonary thromboendarterectomy. (Level of Evidence: C) "

2011 ACC/AHA Guidelines- Recommendations for Initial Anticoagulation for Acute PE (DO NOT EDIT)

Class I

"1. Therapeutic anticoagulation with subcutaneous LMWH, intravenous or subcutaneous UFH with monitoring, unmonitored weight-based subcutaneous UFH, or subcutaneous fondaparinux should be given to patients with objectively confirmed PE and no contraindications to anticoagulation (Level of Evidence: A). "

"2. Therapeutic anticoagulation during the diagnostic workup should be given to patients with intermediate or high clinical probability of PE and no contraindications to anticoagulation (Level of Evidence: C). "

2011 ACC/AHA Guidelines- Recommendations for Fibrinolysis for Acute PE (DO NOT EDIT)

Class I

"1. All patients should be risk stratified. (Level of Evidence: C)"

"2. For most patients (stable) thrombolytic therapy not indicated. (Level of Evidence: B)"

"3. For unstable patients, thrombolytic therapy should be used unless major contraindications. (Level of Evidence: B)"

"4. Systemic therapy preferred over catheter directed lysis. (Level of Evidence: B)"

"5. Short infusions times ( nearly 2 hours) are preferred. (Level of Evidence: B)"

Class III (No Benefit)

"1. Fibrinolysis is not recommended for patients with low-risk PE or submassive acute PE with minor RV dysfunction, minor myocardial necrosis, and no clinical worsening(Level of Evidence: B). "

"2. Fibrinolysis is not recommended for undifferentiated cardiac arrest(Level of Evidence: B). "

Class IIa

"1. Fibrinolysis is reasonable for patients with massive acute PE and acceptable risk of bleeding complications. (Level of Evidence: B) "

Class IIb

"1. Fibrinolysis may be considered for patients with submassive acute PE judged to have clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory insufficiency, severe RV dysfunction, or major myocardial necrosis) and low risk of bleeding complications(Level of Evidence: C)."