Pulmonary embolism treatment approach
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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 a potentially lethal condition, with a mortality rate close to 30 percent without treatment. Thus, prompt therapy is of utmost important. In most cases, anticoagulant therapy is the mainstay of treatment. Acutely, supportive treatments, such as oxygen or analgesia, are often required.
Triage
One of the most important aspects in the care of a patient with acute PE is triage or early risk stratification.
- Patients who are diagnosed with a low-risk PE may require only anticoagulation and medical ward admission.
- On the other hand, patients with massive PE or those with submassive PE who do not improve clinically may benefit from thrombolysis and ICU admission. Initial supportive therapies in these patients may include:
- Respiratory support with oxygen for hypoxemic patients or mechanical ventilation in cases of severe hypoxemia or respiratory failure.
- Hemodynamic support with intravenous fluids or intravenous vasopressors for hypotensive patients. Intravenous fluids should be administered cautiously, as increased right ventricular load can disable the right ventricular oxygen supply-to-demand balance.[1]
Anticoagulation
Anticoagulation in the cornerstone of therapy in acute pulmonary embolism. After initial risk stratification, immediate treatment should be started based on the following:
- Initial treatment with parenteral anticoagulants including subcutaneous Low molecular weight heparin, subcutaneous Fondaparinux or intravenous unfractionated heparin, unless contraindicated.
- Anticoagulation should be started while awaiting confirmation tests, if there is moderate-to-high clinical suspicion of PE.
- Vitamin K antagonists like warfarin should be started the same day and parenteral anticoagulation should be continued for at least 5 days and preferably, until INR in 2.0 or above for 1-2 days.
- In patients with suspected or confirmed heparin-induced thrombocytopenia, lepirudin or argatroban should be used.
- Salient Features:
- Prevent further clot formation, so should be started as early as possible.
- It has no effect on pre-existing clot lysis.
- It has no effect in decreasing the size of thrombus.
- In most cases, anticoagulant therapy is the mainstay of treatment. It includes Heparin, Low molecular weight heparins (such as enoxaparin and dalteparin), or Factor Xa inhibitors (fondaparinux). These are administered initially, while Warfarin therapy is commenced (this may take several days, usually while the patient is in hospital).
Warfarin therapy often requires frequent dose adjustment and monitoring of the INR. In PE, INRs between 2.0 and 3.0 are generally considered ideal.
If another episode of PE occurs under warfarin treatment
- The INR window may be increased to e.g. 2.5-3.5 (unless there are contraindications) or
- Anticoagulation may be changed to a different anticoagulant e.g. low molecular weight heparin.
Anticoagulations should be used with caution, because certain conditions like pericardial tamponade and aortic dissection can mimic Pulmonary Embolism, but the use of anticoagulants is contraindicated in these medical conditions.
Initial anticoagulation
Depending on the clinical presentation, initial therapy is primarily aimed at:
- Restoration of flow through occluded pulmonary arteries, OR
- Prevention of potentially fatal early recurrences.
Most common reason for mortality is recurrent PE, occurring within the few hours of the initial event[2]. Anticoagulant therapy decreases mortality by 2% to 8%, thus making it absolutely necessary to start therapy as soon as possible[3].
Majority of the patients should be started on anticoagulation, with one of the following drugs[4][5]:
- Subcutaneous Low molecular weight heparin
- Intravenous unfractionated heparin.
- Factor Xa Inhibitors (Fondaparinux).
Long-term anticoagulation
Warfarin therapy is usually continued for 3-6 months, or "lifelong" if there have been previous DVTs or PEs, or none of the usual risk factors is present. An abnormal D-dimer level at the end of treatment might signal the need for continued treatment among patients with a first unprovoked pulmonary embolus.[6]
Extended anticoagulation
'Extended treatment should be considered in patients with:
- Active Cancer.
- Unprovoked Pulmonary embolism.
- Recurrent venous thromboembolism.
Indefinite treatment refers to continued anticoagulation without a pre-scheduled stop date.
Anticoaulation may be stopped because of:
- Risk of bleeding.
- Change in patients preference.
Specific circumstances
In patients with an underlying malignancy, low molecular weight heparin is favored over warfarin based on the results of the CLOT trial.[7]
Similarly, pregnant women are often maintained on low molecular weight heparin to avoid the known teratogenic effects of warfarin.
- Subcutaneous or Intravenous Low molecular weight heparin.
- Hemodynamically stable patients.
- Thrombolysis
- High Risk Hemodynamically stable patients.
- Hemodynamically Unstable patients.
- Percutaneous mechanical thrombectomy.
- High risk patients with absolute contraindications to Thrombolytics.
- Patients with failed Thrombolysis.
- Low molecular weight heparin is preferred over Vitamin K antagonist.
Newer anticoagulants
These are a class of anticoagulant drugs which act directly upon Factor X in the coagulation cascade, without using antithrombin as a mediator.Advantages of orally administered direct Xa inhibitors lie in the fact that they have a predictable effect, do not require frequent monitoring or re-dosing, are given through the mouth and not by injection and have few (known) drug interactions. Disadvantages include the currently limited prospective experience and the theoretical interactions with statin medication, as they are metabolized at least in part by the same cytochrome enzyme, CYP3A4.
Thrombolysis
Thrombolysis can be used in cases of severe PE, when surgery is not immediately available or possible (e.g. peri-arrest or during cardiac arrest). The only trial that addressed this issue had 8 patients; the four receiving thrombolysis survived, while the four who received only heparin died.[8]
The use of thrombolysis in moderate PE is still debatable. The aim of the therapy is to dissolve the clot, but there is an attendant risk of bleeding or stroke.[9]
No large clinical trial has demonstrated mortality benefit of thrombolytic therapy. However, it helps in the following ways[10]
- It accelerates clot-lysis, thereby relieving acute PE.
- It improves Right Ventricular function.
- It improves pulmonary perfusion and cardiovascular function.[11]
Major risk factor associated with thrombolytic therapy are:
- Increased risk of major hemorrhage (intracranial hemorrhage, retroperitoneal hemorrhage).
- Massive bleeding leading directly to hospitalization or death.
To read more about dosage, contraindications and guidelines, click here.
Treatment algorithm
| Stabilize the patient | |||||||||||||||||||||||||||||||||||||
| Is anticoagulation contraindicated ? | |||||||||||||||||||||||||||||||||||||
| Yes | No | ||||||||||||||||||||||||||||||||||||
| Diagnostic evaluation | Anticoagulate with SC LMWH or IV UFH | ||||||||||||||||||||||||||||||||||||
| PE excluded | PE confirmed | Diagnostic evaluation | |||||||||||||||||||||||||||||||||||
| No further Treatment | Inferior vena cava filter | PE excluded | PE confirmed | ||||||||||||||||||||||||||||||||||
| Discontinue Anticoagulants | Clinicaly severe enough to need Thrombolysis | ||||||||||||||||||||||||||||||||||||
| Yes | No | ||||||||||||||||||||||||||||||||||||
| Is thrombolytic Contraindicated? | Continue Anticoagulants | ||||||||||||||||||||||||||||||||||||
| 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 | ||||||||||||||||||||||||||||||||||||
Compression Stockings
Treatment Protocol[12]
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) | |||||||||||||||||||
References
- ↑ Mercat A, Diehl JL, Meyer G, Teboul JL, Sors H (1999). "Hemodynamic effects of fluid loading in acute massive pulmonary embolism". Crit. Care Med. 27 (3): 540–4. PMID 10199533. Retrieved 2011-12-12. Unknown parameter
|month=ignored (help) - ↑ Carson JL, Kelley MA, Duff A, Weg JG, Fulkerson WJ, Palevsky HI, Schwartz JS, Thompson BT, Popovich J, Hobbins TE (1992). "The clinical course of pulmonary embolism". N. Engl. J. Med. 326 (19): 1240–5. doi:10.1056/NEJM199205073261902. PMID 1560799. Retrieved 2011-12-12. Unknown parameter
|month=ignored (help) - ↑ Goldhaber SZ, Visani L, De Rosa M (1999). "Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER)". Lancet. 353 (9162): 1386–9. PMID 10227218. Retrieved 2011-12-12. Unknown parameter
|month=ignored (help) - ↑ Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; et al. (2008). "Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest. 133 (6 Suppl): 454S–545S. doi:10.1378/chest.08-0658. PMID 18574272.
- ↑ Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P; et al. (2008). "Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)". Eur Heart J. 29 (18): 2276–315. doi:10.1093/eurheartj/ehn310. PMID 18757870.
- ↑ Palareti G, Cosmi B, Legnani C; et al. (2006). "D-dimer testing to determine the duration of anticoagulation therapy". N. Engl. J. Med. 355 (17): 1780–9. doi:10.1056/NEJMoa054444. PMID 17065639.
- ↑ Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M (2003). "Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer". N Engl J Med. 349 (2): 146–53. PMID 12853587.
- ↑ Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M, Arriaga-Nava R, Valencia S, Rosado-Buzzo A, Pierzo JA, Rosas E. Streptokinase and Heparin versus Heparin Alone in Massive Pulmonary Embolism: A Randomized Controlled Trial. J Thromb Thrombolysis 1995;2:227-229. PMID 10608028.
- ↑ Dong B, Jirong Y, Liu G, Wang Q, Wu T. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev 2006;(2):CD004437. PMID 16625603.
- ↑ Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W (2002). "Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism". N. Engl. J. Med. 347 (15): 1143–50. doi:10.1056/NEJMoa021274. PMID 12374874. Retrieved 2011-12-13. Unknown parameter
|month=ignored (help) - ↑ Levine M, Hirsh J, Weitz J, Cruickshank M, Neemeh J, Turpie AG, Gent M (1990). "A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism". Chest. 98 (6): 1473–9. PMID 2123152. Retrieved 2011-12-21. Unknown parameter
|month=ignored (help) - ↑ Agnelli G, Becattini C (2010). "Acute pulmonary embolism". N Engl J Med. 363 (3): 266–74. doi:10.1056/NEJMra0907731. PMID 20592294.