Pulmonary embolism medical therapy
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Pulmonary Embolism Microchapters |
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Diagnosis |
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Pulmonary Embolism Assessment of Probability of Subsequent VTE and Risk Scores |
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Treatment |
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Follow-Up |
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Special Scenario |
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Trials |
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Case Studies |
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Pulmonary embolism medical therapy On the Web |
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Directions to Hospitals Treating Pulmonary embolism medical therapy |
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Risk calculators and risk factors for Pulmonary embolism medical therapy |
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
In most cases, anticoagulant therapy is the mainstay of treatment. For details, visit treatment approach. This chapter discusses the recommended doses.
Treatment Protocol[1]
Stabilize the patient
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Initial Treatment options (≤5 Days)
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| Long term treatment (≥3 Month) (INR target, 2.0-3.0) | |||||||||||||||||||
| Extended treatment (Indefinite) (INR target, 2.0-3.0 OR 1.5-1.9) | |||||||||||||||||||
Thromboreductive strategies
- Systemic Thrombolysis
- Catheter-Directed Thrombolysis (CDT)/ Pharmacomechanical CDT (PCDT)
- Percutaneous Mechanical and Pharmacomechanical Thrombolysis,
- Thrombolysis in Pediatric Patients
Parenteral Anticoagulants[2]
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.
- Unfractionated heparin is mainly used in patients with known renal insufficiency or those who need close monitoring for bleeding because activated partial thromboplastin time can be checked every 2 hours and doses adjusted.
- The apparent biological half-life of heparin increases from approximately 30 min after an IV bolus of 25 units/kg, to 60 min with an IV bolus of 100 units/kg, to 150 min with a bolus of 400 units/kg.
- Efficacy of heparin in the initial treatment of DVT or PE is highly dependent on dosage.
- Initial dosing of IV heparin for VTE is either weight-based (80 units/kg bolus and 18 units/kg/h infusion) or administered as a bolus of 5,000 units followed by an infusion of at least 32,000 units/d. This is done in order to achieve an aPTT value of 1.5-2.5 of the normal value.
- If heparin is given subcutaneously for the treatment of VTE, there are at least two options:
- An initial IV bolus of 5,000 units followed by 250 units/kg twice daily.
- An initial subcutaneous dose of 333 units/kg followed by 250 units/kg twice daily thereafter.
- The dose for acute coronary syndrome is lower than the dose for the treatment of DVT.
- The main side effects are heparin-induce thrombocytopenia and osteoporosis.
- One major advantage of heparin is that the anticoagulant effects can be reversed with IV protamine sulfate.
- Monitoring
- aPTT monitoring and prolongation correspond with the plasma heparin levels.
- Platelet counts have to be monitored every 2 - 4 days(Heparin induced thrombocytopenia). If one of two platelet counts drops to half of the previous value , HIT should be evaluated.
Low molecular weight heparin
- Low molecular weight heparin is the preferred therapy for PE/DVT(Grade 1A)
- LMWH is administered subcutaneously and is available in various forms like Bemiparin, Dalteparin, Danaparoid, Enoxaparin, Nadroparin, or Tinzaparin.
- The recommended doses for treatment of PE/DVT are:
- Enoxaparin : 1 mg/Kg body weight (twice daily). Dose is 30 mg daily for VTE prophylaxis.
- Tinzaparin : 175 U/Kg body weight (once daily).
- The doses in cases of renal insufficiency are not clear, except Enoxaparin. It is recommended that the dose of Enoxaparin be reduced to 50% of the usual dose in patients with a creatinine clearance of <30 mL/min. In these cases, unfractionated heparin is preferred. (Grade 2C)
- Recommended against anti-Xa monitoring. (Grade 1A)
- Less than 1% risk of HIT
- Recommended against platelet monitoring. (Grade 2C)
Factor Xa Inhibitor[2]
- Fondaparinux binds to antithrombin and inhibits factor Xa.
- It is an acceptable treatment for PE/DVT. (Grade 1A).
- A fixed dose of 2.5 mg daily is used for thromboprophylaxis. In patients with moderate renal insufficiency (creatinine clearance of 30-50 mL/min), the dose should be reduced by 50%.
- Recommended doses for the treatment of DVT or PE are:
- Patients weighing <50 Kg (110 lb): 5 mg (once daily).
- Patients weighing 50 Kg (110 lb) to 110 Kg (220 lb): 7.5 mg (once daily).
- Patients weighing >110 Kg (220 lb): 10 mg (once daily).
- T11/2 in case of normal function is 17 - 21 hours.
- In cases of renal failure with Cr clearance < 30, it should be avoided.
- Recommended against platelet monitoring.
Direct thrombin inhibitors[2]
- Direct thrombin inhibitors bind to thrombin and block its activity. These include hirudin, bivalurudin, and argatroban.
Hirudin
- The recommended dose of IV lepirudin for heparin induced thrombocytopenia is 0.15 mg/kg/h with or without an initial bolus of 0.4 mg/kg.
- The anticoagulant effect of lepirudin in this setting is monitored by using the aPTT, and the dose is adjusted to achieve a target aPTT ratio of 1.5 to 2.5 times control.
- When given for thromboprophylaxis after elective hip replacement surgery, desirudin is given subcutaneously at a dose of 15 mg twice daily without monitoring.
Bivalirudin
- The recommended dose of bivalirudin is a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h for the duration of the procedure.
- Dose reduction should be considered in patients with moderate to severe renal impairment.
Argatroban
- Argatroban is used for the treatment and prevention of heparin-induced thrombocytopenia, associated thrombosis, and for anticoagulation during percutaneous coronary interventions when heparin is contraindicated because of a recent history of heparin-induced thrombocytopenia.
- Argatroban is given as a continuous IV infusion with an initial dose of 1 to 2 mg/kg/min, and the dose is adjusted to maintain the aPTT ratio in the 1.5 to 2.5 range.
Warfarin
- Warfarin is acceptable for DVT/PE. (Grade 1A)
- It should be avoided in pregnanacy. LMWH should be used instead.
- A decision analysis suggests that patients with intermediate and high/likely probabilities of PE benefit from preemptive anticoagulation. [3]
- Heparin should be continued for at least 4 days until INR levels reach 2.0.
- The recommended therapeutic INR during the treatment of DVT or PE with warfarin is 2.0-3.0.
Complications of thrombolytic therapy[4]
- Major hemorrhage - 10%
- Non major hemorrhage - 20%
- Intracranial hemorrhage - 0.5%
Guidelines
ACCP 2012 Guidelines - Recommendations for Initial treatment of Acute PE[5] (DO NOT EDIT)
| 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)" |
ACCP 2012 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)" |
ACCP 2012 Guidelines - Recommendations for anticoagulation in Chronic Thromboembolic Pulmonary Hypertenion[5] (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) " |
ACC/AHA 2011 Guidelines- Recommendations for Initial Anticoagulation for Acute PE[6] (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). " |
Thrombolysis
Thrombolysis is the breakdown (lysis) of blood clots by pharmacological means. It is colloquially referred to as clot busting for this reason. It works by stimulating fibrinolysis by plasmin, through infusion of analogs of tissue plasminogen activator, which is the protein that normally activates plasmin. For treatment recommendations in patients with pulmonary embolism, visit thrombolysis approach.
Dosage
The American College of Cardiology (ACC) Foundation and the American Heart Association (AHA) have proposed the following dosage schedule for the use of thrombolytics: [6]
- Streptokinase
- 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
- 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)
- 100 mg over 2 hr or 0.6 mg/kg over 15 min (maximum dose 50 mg).
Another validated nomogram has proposed the following dosages for thrombolytics[7] in patients with massive and submassive PE:
- 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)
Contraindications
Absolute contraindications
- Hemorrhagic stroke or stroke of unknown origin at any time.
- Ischemic stroke in the last 6 months.
- Central nervous system damage or neoplasms.
- Recent major trauma/surgery/head injury (within the last 3 weeks).
- Gastrointestinal bleeding within the last month.
- Known bleeding.
Relative contraindications
- Transient ischemic attack in preceding 6 months.
- Oral anticoagulant therapy.
- Pregnancy or within 1 week post partum.
- Non-compressible punctures.
- Traumatic resuscitation.
- Refractory hypertension (systolic blood pressure 180 mm Hg).
- Advanced liver disease.
- Infective endocarditis.
- Active peptic ulcer.
ACC/AHA 2011 Guidelines- Recommendations for Fibrinolysis for Acute PE[6] (DO NOT EDIT)
| Class I |
| * All patients should be risk stratified. (Level of Evidence: C) |
| * For most patients (stable) thrombolytic therapy not indicated. (Level of Evidence: B) |
| * For unstable patients, thrombolytic therapy should be used unless major contraindications. (Level of Evidence: B) |
| * Systemic therapy preferred over catheter directed lysis. (Level of Evidence: B) |
| * 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)." |
Guidelines Resources
- Guidelines on the management of Pulmonary embolism: Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension[6]
- Guidelines on the management of Pulmonary embolism: Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension[6]
References
- ↑ Agnelli G, Becattini C (2010). "Acute pulmonary embolism". The New England Journal of Medicine. 363 (3): 266–74. doi:10.1056/NEJMra0907731. PMID 20592294. Retrieved 2012-10-06. Unknown parameter
|month=ignored (help) - ↑ 2.0 2.1 2.2 Garcia DA, Baglin TP, Weitz JI, Samama MM (2012). "Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e24S–43S. doi:10.1378/chest.11-2291. PMID 22315264. Unknown parameter
|month=ignored (help) - ↑ Blondon M, Righini M, Aujesky D, Le Gal G, Perrier A (2012). "Utility of preemptive anticoagulation in patients with suspected pulmonary embolism: a decision analysis". Chest. doi:10.1378/chest.11-2694. PMID 22383664.
- ↑ "Thrombolysis Compared With Heparin for the Initial Treatment of Pulmonary Embolism". Retrieved 2012-10-06.
- ↑ 5.0 5.1 5.2 Kearon C, Akl EA, Comerota AJ; et al. (2012). "Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e419S–94S. doi:10.1378/chest.11-2301. PMID 22315268. Unknown parameter
|month=ignored (help) - ↑ 6.0 6.1 6.2 6.3 6.4 Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ; et al. (2011). "Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association". Circulation. 123 (16): 1788–830. doi:10.1161/CIR.0b013e318214914f. PMID 21422387.
- ↑ Fengler BT, Brady WJ (2009). "Fibrinolytic therapy in pulmonary embolism: an evidence-based treatment algorithm". Am J Emerg Med. 27 (1): 84–95. doi:10.1016/j.ajem.2007.10.021. PMID 19041539.