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__NOTOC__
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{| class="infobox" style="float:right;"
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| [[File:Siren.gif|30px|link=Pulmonary embolism resident survival guide]]|| <br> || <br>
| [[Pulmonary embolism resident survival guide|'''Resident'''<br>'''Survival'''<br>'''Guide''']]
|}
{{Pulmonary embolism}}
{{Pulmonary embolism}}
'''Editor(s)-In-Chief:''' {{ATI}}, [[C. Michael Gibson, M.S., M.D.]] [mailto:charlesmichaelgibson@gmail.com]; {{AE}} {{CZ}}  
'''Editor(s)-In-Chief:''' {{ATI}}, [[C. Michael Gibson, M.S., M.D.]] [mailto:charlesmichaelgibson@gmail.com]; {{AE}} {{CZ}}; {{Rim}}
==Overview==
==Overview==
Pulmonary embolism patients are at increased risk of a second attack of PE. If un-treated, almost 1/3 of the patients die, usually from recurrent PE. Therefore, a patient should be discharged only after proper diagnosis and discharge medication.
While hospital admission is necessary for patients who have a [[pulmonary embolism#Massive Pulmonary Embolism|massive]] or [[pulmonary embolism#Submassive Pulmonary Embolism|submassive pulmonary embolism]] (PE), patients with [[pulmonary embolism#Low-Risk Pulmonary Embolism|low risk PE]] who have no evidence of [[hypotension]], [[RV dysfunction|right ventricular dysfunction]], or myocardial [[necrosis]] can be discharged early on and put on an outpatient treatment regimen.<ref name="pmid20592294">{{cite journal| author=Agnelli G, Becattini C| title=Acute pulmonary embolism. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 3 | pages= 266-74 | pmid=20592294 | doi=10.1056/NEJMra0907731 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20592294  }} </ref> 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 outpatient anticoagulation therapy is [[vitamin K antagonist]]s (VKA); whereas the first line treatment among cancer patients is [[low molecular weight heparin]] ([[LMWH]]).
Information pertaining to the safety of outpatient treatment of a pulmonary embolism is still inadequate due to the lack of a randomized control trial comparing in-patient and outpatient management.


== Discharge Care ==
== Discharge Care ==
=== Discharge Criteria ===
=== Discharge Criteria ===
* The mortality of low risk PE, submassive (intermediate risk) PE, and massive (high risk) PE increases from <3%, to 3-15%, to >15% respectively.  Given the elevated rate of mortality in cases of submassive and massive PE, hospital admission is necessary for patients who are stratified within these categories.ref name="pmid18757870">{{cite journal |author=Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP |title=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) |journal=Eur. Heart J. |volume=29|issue=18 |pages=2276–315 |year=2008 |month=September|pmid=18757870 |doi=10.1093/eurheartj/ehn310|url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18757870|accessdate=2011-12-07}}</ref>  Hemodynamic stability is not the criteria for discharge. Patients who are hemodynamically stable but have [[RV dysfunction|right ventricular dysfunction]] (stratified as submassive PE), should be admitted.  
* The mortality of [[pulmonary embolism#Low-Risk Pulmonary Embolism|low risk PE]], [[pulmonary embolism#Submassive Pulmonary Embolism|submassive (intermediate risk) PE]], and [[pulmonary embolism#Massive Pulmonary Embolism|massive (high risk) PE ]] increases from <3%, to 3-15%, to >15% respectively.<ref name="pmid18757870">{{cite journal |author=Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP |title=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) |journal=Eur. Heart J. |volume=29|issue=18 |pages=2276–315 |year=2008 |month=September|pmid=18757870 |doi=10.1093/eurheartj/ehn310|url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18757870|accessdate=2011-12-07}}</ref> Given the elevated rate of mortality in cases of [[pulmonary embolism#Submassive Pulmonary Embolism|submassive]] and [[pulmonary embolism#Massive Pulmonary Embolism|massive]] PE, hospital admission is necessary for patients who are stratified within these categories.<ref name="pmid18757870">{{cite journal |author=Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP |title=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) |journal=Eur. Heart J. |volume=29|issue=18 |pages=2276–315 |year=2008 |month=September|pmid=18757870 |doi=10.1093/eurheartj/ehn310|url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18757870|accessdate=2011-12-07}}</ref>  Hemodynamic stability is not the criteria for discharge. Patients who are hemodynamically stable but have [[RV dysfunction|right ventricular dysfunction]] (stratified as submassive PE), should be admitted.  


* Patients with low risk PE whom have no evidence of [[hypotension]], [[RV dysfunction|Right ventricular dysfunction]], or myocardial [[necrosis]] can be discharged and put on out-patient treatment.<ref name="pmid20592294">{{cite journal| author=Agnelli G, Becattini C| title=Acute pulmonary embolism. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 3 | pages= 266-74 | pmid=20592294 | doi=10.1056/NEJMra0907731 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20592294  }} </ref>
* Patients with [[pulmonary embolism#Low-Risk Pulmonary Embolism|low risk PE]] who have no evidence of [[hypotension]], [[RV dysfunction|right ventricular dysfunction]], or myocardial [[necrosis]] can be discharged early on and put on an outpatient treatment regimen.<ref name="pmid20592294">{{cite journal| author=Agnelli G, Becattini C| title=Acute pulmonary embolism. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 3 | pages= 266-74 | pmid=20592294 | doi=10.1056/NEJMra0907731 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20592294  }} </ref>


=== Discharge Medications ===
=== Discharge Medications ===
====Initial Anticoagulation Therapy====
====Initial Anticoagulation Therapy====
*Low risk PE patients can have an early discharge and outpatient treatment.  For more details about the choices of treatment, click [[Pulmonary embolism treatment algorithm|here]].
* [[Pulmonary embolism#Low-Risk Pulmonary Embolism|Low risk PE]] patients can have an early discharge and outpatient treatment.  For more details about the choices of treatment, click [[Pulmonary embolism treatment algorithm|here]].


====Long Term Anticoagulation Therapy====
====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 antagonist]]s (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).<ref name="pmid22315268">{{cite journal| author=Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ et al.| title=Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal=Chest | year= 2012 | volume= 141 | issue= 2 Suppl | pages= e419S-94S | pmid=22315268 | doi=10.1378/chest.11-2301 | pmc=PMC3278049 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22315268  }} </ref>
* 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 antagonist]]s (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).<ref name="pmid22315268">{{cite journal| author=Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ et al.| title=Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal=Chest | year= 2012 | volume= 141 | issue= 2 Suppl | pages= e419S-94S | pmid=22315268 | doi=10.1378/chest.11-2301 | pmc=PMC3278049 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22315268  }} </ref>
 
Shown below is an algorithm depicting the long term outpatient anticoagulation therapy for patients with PE.<ref name="pmid22315268">{{cite journal| author=Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ et al.| title=Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal=Chest | year= 2012 | volume= 141 | issue= 2 Suppl | pages= e419S-94S | pmid=22315268 | doi=10.1378/chest.11-2301 | pmc=PMC3278049 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22315268  }} </ref>


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''Note that [[edoxaban]]<ref name="pmid23991658">{{cite journal| author=Hokusai-VTE Investigators. Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S et al.| title=Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. | journal=N Engl J Med | year= 2013 | volume= 369 | issue= 15 | pages= 1406-15 | pmid=23991658 | doi=10.1056/NEJMoa1306638 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23991658  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24445714 Review in: Ann Intern Med. 2014 Jan 21;160(2):JC4]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24638182 Review in: Ann Intern Med. 2014 Mar 18;160(6):JC4] </ref> has been evaluated for the treatment of [[VTE]] and is currently seeking approval for this indication.''
''Note that [[edoxaban]]<ref name="pmid23991658">{{cite journal| author=Hokusai-VTE Investigators. Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S et al.| title=Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. | journal=N Engl J Med | year= 2013 | volume= 369 | issue= 15 | pages= 1406-15 | pmid=23991658 | doi=10.1056/NEJMoa1306638 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23991658  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24445714 Review in: Ann Intern Med. 2014 Jan 21;160(2):JC4]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24638182 Review in: Ann Intern Med. 2014 Mar 18;160(6):JC4] </ref> has been evaluated for the treatment of [[VTE]] and is currently seeking approval for this indication.''


* An ongoing trial is discussing whether or not to withhold anticoagulation among patients with subsegmental PE. (ClinicalTrials.gov number, NCT01455818) [http://clinicaltrials.gov/ct2/show/NCT01455818?term=nct01455818&rank=1]. The result of this trial will further enlighten physicians about discharge care in PE patients.
* After treatment in the hospital, the patient should continue [[anticoagulation therapy]] 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.<ref name="pmid17065639">{{cite journal |author=Palareti G, Cosmi B, Legnani C, ''et al'' |title=D-dimer testing to determine the duration of anticoagulation therapy |journal=N. Engl. J. Med. |volume=355 |issue=17 |pages=1780-9 |year=2006 |pmid=17065639 |doi=10.1056/NEJMoa054444}}</ref>
* Long-term treatment is usually recommended with vitamin K antagonists like [[warfarin]], unless [[warfarin]] is contraindicated or in cases of [[cancer]] or [[pregnancy]]..
* 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:
* Unprovoked PE: The patient's risk for recurrent PE  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
* 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 [[Thrombophilia#Laboratory testing|thrombophilias]].
 
==== Specific Circumstances ====
* Malignancy: [[Low molecular weight heparin]] is favored over warfarin based on the results of the CLOT trial.<ref>{{cite journal | author=Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M|title=Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. | journal=N Engl J Med| year=2003 | pages=146-53 | volume=349 | issue=2  | id=PMID 12853587}}</ref>
* 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.


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
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{{WS}}
 
[[Category:Hematology]]
[[Category:Hematology]]
[[Category:Pulmonology]]
[[Category:Pulmonology]]
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[[Category:Emergency medicine]]
[[Category:Emergency medicine]]
[[Category:Intensive care medicine]]
[[Category:Intensive care medicine]]
[[Category:Primary care]]
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Latest revision as of 23:53, 29 July 2020
Resident
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Guide

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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

While hospital admission is necessary for patients who have a massive or submassive pulmonary embolism (PE), patients with low risk PE who have no evidence of hypotension, right ventricular dysfunction, or myocardial necrosis can be discharged early on and put on an outpatient treatment regimen.[1] 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 outpatient anticoagulation therapy is vitamin K antagonists (VKA); whereas the first line treatment among cancer patients is low molecular weight heparin (LMWH).

Discharge Care

Discharge Criteria

Discharge Medications

Initial Anticoagulation Therapy

  • Low risk PE patients can have an early discharge and outpatient treatment. For more details about the choices of treatment, click here.

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).[3]

Shown below is an algorithm depicting the long term outpatient anticoagulation therapy for patients with PE.[3]

 
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low or moderate
 
High
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extended therapy
 
Do not extend the therapy beyond the initial 3 months
 
 
 
 
 
 


Note that edoxaban[4] has been evaluated for the treatment of VTE and is currently seeking approval for this indication.

  • After treatment in the hospital, the patient should continue anticoagulation therapy 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.[5]
  • Long-term treatment is usually recommended with vitamin K antagonists like warfarin, unless warfarin is contraindicated or in cases of cancer or pregnancy..
  • 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:

  • Unprovoked PE: The patient's risk for recurrent PE 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
  • 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

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.

References

  1. ↑ 1.0 1.1 Agnelli G, Becattini C (2010). "Acute pulmonary embolism". N Engl J Med. 363 (3): 266–74. doi:10.1056/NEJMra0907731. PMID 20592294.
  2. ↑ 2.0 2.1 Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP (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. Retrieved 2011-12-07. Unknown parameter |month= ignored (help)
  3. ↑ 3.0 3.1 Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ; 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. PMC 3278049. PMID 22315268.
  4. ↑ Hokusai-VTE Investigators. Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S; et al. (2013). "Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism". N Engl J Med. 369 (15): 1406–15. doi:10.1056/NEJMoa1306638. PMID 23991658. Review in: Ann Intern Med. 2014 Jan 21;160(2):JC4 Review in: Ann Intern Med. 2014 Mar 18;160(6):JC4
  5. ↑ 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.
  6. ↑ 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.

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