Pulmonary embolism: Difference between revisions

(48 intermediate revisions by 11 users not shown)
Line 1: Line 1:
''See [[Pulmonary embolism in pregnancy]] for pregnancy specific information.''<ref>D-Dimer Concentrations in Normal Pregnancy: New Diagnostic Thresholds Are Needed. Kline et all. Clinical Chemistry May 2005 vol. 51 no. 5 825-829 http://www.clinchem.org/content/51/5/825.long</ref>
''See [[pulmonary embolism in pregnancy]] for pregnancy specific information.''<ref>D-Dimer Concentrations in Normal Pregnancy: New Diagnostic Thresholds Are Needed. Kline et all. Clinical Chemistry May 2005 vol. 51 no. 5 825-829 http://www.clinchem.org/content/51/5/825.long</ref>


==Background==
==Background==
Line 5: Line 5:


{{PE types}}
{{PE types}}
=== Epidemiology ===
* The best estimates indicate that 350,000 to 600,000 Americans each year suffer from DVT and PE<ref>Mozaffarien D et al.  Heart disease and stroke statistics - 2015 report from the American Heart Association. Circulation. 2015;131:d29-e322</ref>
* Survival<ref>U. S. Department of Health and Human Services. www.ncbi.nlm.nih.gov/blooks/NBK44178. The surgeon general's call to prevent deep vein thrombosis and pulmonary embolism.  2008</ref>
**PE is the 3rd leading cause of cardiovascular morbidity and mortality
**At least 100,000 deaths per year may be directly or indirectly related to DVT and PE
**For almost one quarter of PE patients, the initial clinical presentation is sudden death
**PE is an independent predictor of reduced survival for ≤3 months
**One of the leading causes of out-of-hospital, non-trauma related sudden deaths <ref>Tintinalli, J. E. (2016). Venous Thromboembolism In J.E. Tintinali (8th Ed.), Tintinalli's Emergency Medicine: A Comprehensive Study Guide  (pp. 389-390). New York, New York: McGraw Hill Education</ref>


==Clinical Features==
==Clinical Features==
Line 13: Line 22:
{{SOB DDX}}
{{SOB DDX}}


==Workup (by Pretest Probability)==
==Workup==
===Assessing Pretest Probability===
===Assessing Pretest Probability===
''Objective criteria (Geneva, Wells, etc.) is equal to gestalt in assessing pre-test probability<ref name="ACEP">ACEP Clinical Policy for Pulmonary Embolism [http://www.acep.org/Content.aspx?id=80787/ full text]</ref> (ACEP Level B)''
*''Objective criteria (Geneva, Wells, etc.) is equal to gestalt in assessing pre-test probability<ref name="ACEP">ACEP Clinical Policy for Pulmonary Embolism [http://www.acep.org/Content.aspx?id=80787/ full text]</ref> (ACEP Level B)''
*Initial Wells study and prospective validation <ref> Wolf SJ, et al. Prospective validation of Wells Criteria in the evaluation of patients with suspected pulmonary embolism. Ann Emerg Med. 2004 Nov;44(5):503-10</ref> used a three tier system (low 0-1, intermediate 2-6, high >6) to establish pretest probability with a small sample size
*The larger Christopher Study group used a larger sample size to derive the simplified dichotomized/two tier model below<ref>van Belle A et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295(2):172-179. doi:10.1001/jama.295.2.172</ref>


{{Wells Score}}
{{Wells Score}}


====Less common risks====
===Low-Probability Testing in the ED===
*''[[PERC Rule]] negative'', then no further workup<ref name="ACEP" /> (ACEP Level B)
**Avoid CT pulmonary angiography in low pretest probability patients that are either PERC rule negative or have a negative d-dimer ([[Choosing wisely ACEP|ACEP choosing wisely]])
**D-dimer NPV is 99.5%<ref>Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple</ref>
*''[[PERC Rule]] positive'', then [[D-dimer]] (see Moderate-Probability Testing below)<ref name="ACEP" />  (ACEP Level B)
**Can also consider using Wells score as above to determine further testing
 
===Adjusted D-Dimer to Higher Threshold===
*For certain patients a higher d-dimer can be used<ref>Flex your D-dimer Taming of the SRU http://www.tamingthesru.com/blog/diagnostics/flex-your-d-dimer</ref>
*[https://wikem.org/wiki/Age_adjusted_D-dimer Age Adjusted D-Dimer]
*[https://www.mdcalc.com/years-algorithm-pulmonary-embolism-pe YEARS Algorithm]
*[https://www.nejm.org/doi/full/10.1056/NEJMoa1909159 PEGeD]
 
===Less common risk factors===
*HIV (protein wasting nephropathy)
*HIV (protein wasting nephropathy)
*[[Nephrotic Syndrome]]
*[[Nephrotic Syndrome]]
*[[SLE]] with anti-cardiolipan Ab
*[[SLE]] with anti-cardiolipin Ab
*Exogenous hormones (specifically estrogen)
*Exogenous hormones (specifically estrogen)
*Factor V Leiden
*homozygous [[Factor V Leiden]]
*Antithrombin III deficiency
*Antithrombin III deficiency
*Protein C deficiency
*Protein C deficiency
Line 30: Line 54:
*Hyperhomocysteinemia
*Hyperhomocysteinemia


===Low Probability Testing===
===Evaluate bleeding risk (HAS-BLED)===
*''[[PERC Rule]] negative'', then no further workup<ref name="ACEP" /> (ACEP Level B)
*HAS-BLED score (developed to evaluate bleeding risk for anticoagulation in Afib) can also identify patients with acute VTE at high risk for bleeding complications within 6 months<ref>Kooiman J et al. The HAS-BLED score identifies patients with acute venous thromboembolism at high risk of major bleeding complications during the first six months of anticoagulant treatment. PLOS ONE. 2015 Apr 23;10(4):e0122520. doi: 10.1371/journal.pone.0122520. eCollection 2015.</ref>
**Avoid CT pulmonary angiography in low pretest probability patients that are either PERC rule negative or have a negative d-dimer ([[Choosing wisely ACEP|ACEP choosing wisely]])
{| {{table}}
**D-dimer NPV is 99.5%<ref>Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple</ref>
| align="center" style="background:#f0f0f0;"|'''Risk Factor'''
*''[[PERC Rule]] positive'', then [[d-dimer]] (See moderate probability below)<ref name="ACEP" />  (ACEP Level B)
| align="center" style="background:#f0f0f0;"|'''Point'''
 
|-
===Moderate Probability Testing===
| Hypertension||1
*[[D-dimer]] (consider [[age adjusted D-dimer]])
|-
**Positive, continue testing (see high risk below)
| Abnormal renal and/or hepatic function||1 point each
**Negative, no further testing
|-
***However, it is unclear whether d-dimer alone is sufficient to rule-out PE<ref name="ACEP" /> (ACEP Level C)
| Stroke||1
 
|-
===High Probability Testing===
| Bleeding tendency/predisposition||1
'''Consider anticoagulation before imaging!'''
|-
 
| Labile INR on warfarin||1
===Post-Test Probability Calculations===
|-
| Elderly (age >65 years)||1
|-
| Drugs (aspirin or NSAIDs) and/or alcohol||1 point each
|-
|}
*When applied to VTE patients on vitamin K-antagonists, NOT DOACs (in first 6 months of treatment):
**Score 0-2 = 1.3% incidence of major bleeds
**Score 3+ = 9.6% incidence of major bleeds
*Other bleeding risk models include the RIETE score (validated in patients taking VKA or rivaroxaban) and VTE-BLEED score (validated in patients taking warfarin and edoxaban).


===Initial Management While Awaiting Workup<ref>ACCP 9th Edition of the Antithrombotic Therapy Guidelines: Kearon C et al. Antithrombotic therapy for VTE disease. Chest. 2012;141:e419s – e494s. doi: 10.1378/chest.11-2301.</ref>===
*based on ACCP 2016 Guidelines
{| class="wikitable"
{| class="wikitable"
!  
!Clinical suspicion !! Management
! Pretest
! - LR
! Posttest
|-
|-
| Wells < 4 + PERC
| Low || Do not treat with anticoagulation while awaiting diagnostic test results
| 12%
| 0.12
| 1.6%
|-
|-
| Wells < 4 + Neg Dimer
| Medium || Treat with parenteral anticoagulation if the results of diagnostic tests are expected to be delayed ≥ 4 hours
| 12%
| 0.01
| 0.14%
|-
|-
| Wells < 4 + AA Dimer
| High || Treat with parenteral anticoagulation while awaiting diagnostic test results
| 12%
| 0.06
| 0.81%
|-
|-
| Wells < 2 + PERC
| 2%
| 0.01
| 0.24%
|-
| Wells < 2 + Neg Dimer
| 2%
| 0.06
| 0.02%
|-
| Wells < 2 + AA Dimer
| 2%
| 0.12
| 0.12
|}
|}


==Diagnosis==
==Diagnosis==
===Definitive Imaging===
[[File:SaddlePE.png|thumb|A large pulmonary embolism at the bifurcation of the pulmonary artery (saddle embolism).]]
*CTA if GFR >60
===Definitive Diagnostic Imaging===
*V/Q if GFR <60
*CTA Chest if GFR >60
*V/Q scan if GFR <60
**Will be nondiagnostic if patient has effusion, pneumonia, or other airspace disease
**Will be nondiagnostic if patient has effusion, pneumonia, or other airspace disease
*If imaging negative, perform additional diagnostic testing (eg, D-dimer, LE vasc US, VQ, traditional pulmonary arteriography) prior to exclusion of VTE<ref name="ACEP" /> (ACEP Level C)
*If imaging negative, perform additional diagnostic testing (e.g. lower extremity Doppler US, V/Q scan, and/or traditional pulmonary angiogram) prior to exclusion of VTE<ref name="ACEP" /> (ACEP Level C)
**A negative d-dimer in combination with a negative CTA theoretically provides a post-test probability of VTE less than 1%
**A negative d-dimer in combination with a negative CTA theoretically provides a post-test probability of VTE less than 1%


===Other Possible Diagnostic Findings===
===Other Possible Diagnostic Findings===
[[File:dsign.gif|thumbnail|D Sign<ref>http://www.thepocusatlas.com/right-ventricle</ref>]]
[[File:dsign.gif|thumb|D Sign<ref>http://www.thepocusatlas.com/right-ventricle</ref>]]
[[File:Hamptons.jpg|thumbnail|Hampton's Hump]]
[[File:Hamptons.jpg|thumb|Hampton's Hump]]
*[[ECG]] (sbnormal in 70% of [[PE]] patients<ref>Marchick, MR et al. 12-lead ECG findings of pulmonary hypertension occur more frequently in emergency department patients with pulmonary embolism than in patients without pulmonary embolism. Ann Emerg Med. 2010 Apr;55(4):331-5.</ref>)
*[[ECG]] (abnormal in 70% of PE <ref>Marchick, MR et al. 12-lead ECG findings of pulmonary hypertension occur more frequently in emergency department patients with pulmonary embolism than in patients without pulmonary embolism. Ann Emerg Med. 2010 Apr;55(4):331-5.</ref> and associated with an adverse prognosis<ref>Agarwal A et al. Acute management of pulmonary embolism. https://www.acc.org/latest-in-cardiology/articles/2017/10/23/12/12/acute-management-of-pulmonary-embolism. 2017</ref>)
**Sinus tachycardia is most common finding
**T-wave inversions (34%)<ref>Co I, Eilbert W, Chiganos T. New Electrocardiographic Changes in Patients Diagnosed with Pulmonary Embolism. J Emerg Med. 2017 Mar;52(3):280-285. doi: 10.1016/j.jemermed.2016.09.009. Epub 2016 Oct 11. PMID: 27742402.</ref>
**T-wave inversion in anterior/septal leads + inferior leads<ref>Kosuge M, Kimura K, Ishikawa T, et al. Electrocardiographic differentiation between acute pulmonary embolism and acute coronary syndromes on the basis of negative T waves. Am J Cardiol 2007; 99: 817–821</ref>
***Anterior/septal leads (V1-V4) and inferior leads<ref>Kosuge M, Kimura K, Ishikawa T, et al. Electrocardiographic differentiation between acute pulmonary embolism and acute coronary syndromes on the basis of negative T waves. Am J Cardiol 2007; 99: 817–821</ref>
**Nonspecific ST changes, S1Q3T3 (develops due to strain on RV)
**T-wave flattening (30%)
**RBBB or new incomplete RBBB.<ref>Shopo, JD et al. Findings from 12-lead electrocardiography that predict circulatory shock in pulmonary embolism; a systematic review and meta-analysis. Acad Emerg Med. 2015 Oct;22(10):1127-37</ref>
**Sinus Tachycardia (27%)
**New right axis deviation
**Right axis deviation (11%)
**Atrial fibrillation
**St-segment changes in V1-V4 (9%)
**S1Q3TS RV strain pattern (4%)
**New-onset atrial arrhythmias (e.g. atrial fibrillation)
**New RBBB (complete or incomplete) <ref>Shopo, JD et al. Findings from 12-lead electrocardiography that predict circulatory shock in pulmonary embolism; a systematic review and meta-analysis. Acad Emerg Med. 2015 Oct;22(10):1127-37</ref>
**QR pattern in V1
*[[CXR]] (abnormal in 70%)
*[[CXR]] (abnormal in 70%)
**Atelectasis is most common (esp >24 hrs after onset of symptoms)
**Atelectasis is most common (esp >24 hrs after onset of symptoms)
Line 107: Line 121:
**Hampton's Hump  
**Hampton's Hump  
**Westermark's sign<ref>Sreenivasan S, Bennett S, Parfitt VJ. Images in cardiovascular medicine. Westermark's and Palla's signs in acute pulmonary embolism. Circulation. 2007 Feb 27;115(8):e211. [http://circ.ahajournals.org/content/115/8/e211.long full text]</ref>  
**Westermark's sign<ref>Sreenivasan S, Bennett S, Parfitt VJ. Images in cardiovascular medicine. Westermark's and Palla's signs in acute pulmonary embolism. Circulation. 2007 Feb 27;115(8):e211. [http://circ.ahajournals.org/content/115/8/e211.long full text]</ref>  
*Transthoracic echo
*[[Formal echocardiography|Formal transthoracic echo]] or [[Cardiac ultrasound|bedside cardiac ultrasound]]
**Can help diagnosis in equivocal cases
**May see signs of right heart strain (bowing of septum into LV; Aka D Sign)
**May see signs of right heart strain (bowing of septum into LV; Aka D Sign)
***Right ventricular strain is associated with statistically significant worse outcome<ref>Taylor, RA, et al. Point-of-care focused cardiac ultrasound for prediction of pulmonary embolism adverse outcomes. The Journal of Emergency Medicine. 2013; 45(3):392–399.</ref>
**McConnel's sign (akinesis of RV base/free wall with sparing of apex)
**McConnel's sign (akinesis of RV base/free wall with sparing of apex)
**Lateral right ventricular wall diameter of <5mm is suggestive of acute pulmonary hypertension while >5mm is suggestive of chronic pulmonary hypertension<ref>Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010; 23(7):685-713.</ref>
**Lateral right ventricular wall diameter of <5mm is suggestive of acute pulmonary hypertension while >5mm is suggestive of chronic pulmonary hypertension<ref>Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010; 23(7):685-713.</ref>
====Bedside Ultrasound====
*[[Cardiac ultrasound|Ultrasound]] can help diagnosis in equivocal cases
*Assess for right ventricular strain (RVS) and McConnell's sign
*RVS is associated with statistically significant worse outcome<ref>Taylor, RA, et al. Point-of-care focused cardiac ultrasound for prediction of pulmonary embolism adverse outcomes. The Journal of Emergency Medicine. 2013; 45(3):392–399.</ref>
====Other Modalities====
*SPECT  
*SPECT  
**Combination of noncontrast CT chest with V/Q scan
**Combination of noncontrast CT chest with V/Q scan
Line 125: Line 134:
==Management==
==Management==
===Supportive care===
===Supportive care===
*Give [[IVF]] as necessary to increase preload while frequently assessing volume status
*Oxygen therapy (maintain SpO2 ≥90% unless otherwise indicated)
*Hemodynamic support (e.g. IVF, pressors)
**Consider gentle fluid challenge of 500ml normal saline bolus to improve cardiac index in select patients<ref>Mercat A et al. Hemodynamic effects of fluid loading in acute massive pulmonary embolism. Crit Care Med. 1999 Mar;27(3):540-4</ref>
**Experimental studies suggest that aggressive volume expansion provides little benefit and may worsen RV function in those with acutely elevated RV afterload and acutely increased pulmonary HTN<ref>Konstantinides SV et al. ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69 doi: 10.1093/eurheartj/ehu283</ref>


===Anticoagulation===
===Anticoagulation===
*Always consider [[Pulmonary_embolism#Evaluate_bleeding_risk_.28HAS-BLED.29|bleeding risk]] when determining risks/benefits of initiating anticoagulation
*Treatment options include any of the following anticoagulations which are indicated for all patients with confirmed [[PE]] or high clinical suspicion (do not wait for imaging).
*Treatment options include any of the following anticoagulations which are indicated for all patients with confirmed [[PE]] or high clinical suspicion (do not wait for imaging).
*The Feb. 2016 CHEST Guideline recommends clinical surveillance over anticoagultation for subsegmental [[PE]] with no proximal [[DVT]] at low risk for recurrent VTE based on [[EBQ:Evidence_Levels| level 2C]] evidence<ref>Kearon, Clive, et al. "Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report." Chest (2016).[[http://www.cercp.org/images/stories/recursos/articulos_docs_interes/guia_tto_antitrombotico_tv_2016.pdf fulltext]]</ref>
 
*'''[[LMWH]] SC'''
{| {{table}}
**1st line for most hemodynamically stable patients
| align="center" style="background:#f0f0f0;"|'''Name'''
**Contraindicated in renal failure
| align="center" style="background:#f0f0f0;"|'''[[LMWH]] SC'''
**Enoxaparin 1mg/kg SC q12h
| align="center" style="background:#f0f0f0;"|'''[[Unfractionated Heparin]]'''
**Dalteparin 200 IU/kg SC q24h, max 18,000 IU
| align="center" style="background:#f0f0f0;"|'''[[Dabigatran]]'''
*'''[[Unfractionated Heparin]]'''
| align="center" style="background:#f0f0f0;"|'''[[Rivaroxaban]]'''
**80 units/kg bolus; then 18 units/kg/hr
| align="center" style="background:#f0f0f0;"|'''[[Apixaban]]'''
**Check PTT after 6hr; adjust infusion to maintain PTT at 1.5-2.5x control
| align="center" style="background:#f0f0f0;"|'''[[Coumadin]]'''
**Benefit of Heparin is the short half life and easy ability to turn off the infusion. Consider
|-
**Patients with morbid obesity or anasarca may have poor  sc absorption with LMWH
|'''Initial Dose'''
**No need for renal dosing
||
**The prefered anticoagulation if thrombolysis is being considered or if there is a bleeding risk or trauma and anticoagulation will need to be emergently discontinued
*[[Enoxaparin]] 1mg/kg SC q12h  
*[[Dabigatran]]
*[[Dalteparin]] 200 IU/kg SC q24h, max 18,000 IU
**A direct thrombin inhibitor
||
**Approved by the FDA in 2014 for the treatment of [[DVT]]and PE
*80 units/kg bolus; then 18 units/kg/hr continuous infusion
**Dabigatran was noninferior to warfarin in reducing [[DVT]]and PE<ref>Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009; 361(24):2342-52. </ref><ref>Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014; 129(7):764-72.</ref>
||
*'''[[Rivaroxaban]]'''
*Parenteral anticoagulation for 5-10 days; then 150mg twice daily
**Factor Xa inhibitors
||
**Approved by the FDA in November 2012 for the treatment of [[DVT]]or PE
*15mg twice daily for 3 weeks, then 20mg once daily
**Associated with less bleeding, particularly in elderly patients and those with moderate renal impairment compared to standard treatments<ref>Hughes S. Rivaroxaban Stands up to standard anticoagulation for VTE treatment. Medscape Medical News. December 13, 2012.</ref><ref>Buller HR, on behalf of the EINSTEIN Investigators. Oral rivaroxaban for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN [[DVT]]and EINSTEIN [[PE]] studies [abstract 20]. Presented at: 54th Annual Meeting and Exposition of the American Society of Hematology; December 8, 2012; Atlanta, Ga.</ref>
||
*[[Apixaban]]
*10mg twice daily for 1 week, then 5mg twice daily
**Factor Xa inhibitor
||
**Approved for treatment of [[PE]] in August 2014
*Cannot be administered alone for acute PE. Usual starting dose 5mg PO
**Studies show 16% reduction in VTE related death compared to standard therapy<ref>Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013; 369(9):799-808.</ref><ref>Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013; 368(8):699-708.</ref>
|-
*Vit K antagonist - [[Coumadin]]
| '''Benefits'''
**3-6 mo if time limited risk factor (post-op, trauma, estrogen use)
||
**6 mo - life if idiopathic etiology or recurrent
*1st line for most hemodynamically stable patients
**INR target 2.5
*Preferred in those with cancer, liver disease, coagulopathy, pregnancy
**Temporary hypercoagulable state for approx 5 days
||
**Initial dose is 5 mg PO
*Short half-life
*Preferred if rapid reversal is needed (e.g. considering thrombolytics or with bleeding risk/trauma)
*No need for renal dosing
||
*Noninferior to warfarin in reducing [[DVT]] and PE <ref>Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009; 361(24):2342-52. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014; 129(7):764-72.</ref>
||
*Preferred if parenteral therapy to be avoided
*Associated with less bleeding, particularly in elderly patients and those with moderate renal impairment compared to standard treatments <ref>Hughes S. Rivaroxaban Stands up to standard anticoagulation for VTE treatment. Medscape Medical News. December 13, 2012.Buller HR, on behalf of the EINSTEIN Investigators. Oral rivaroxaban for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN [[DVT]] and EINSTEIN [[PE]] studies [abstract 20]. Presented at: 54th Annual Meeting and Exposition of the American Society of Hematology; December 8, 2012; Atlanta, Ga.</ref>
||
*Preferred if parenteral therapy to be avoided or if history of GI bleeding
*Studies show 16% reduction in VTE related death compared to standard therapy <ref>Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013; 369(9):799-808.Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013; 368(8):699-708.</ref>
||
*Preferred in renal disease, history of poor compliance, or history of GI bleed
|-
| '''Contraindications'''
||
*Severe renal impairment (CrCl <30 mL/min)
*Patients with morbid obesity or anasarca may have poor absorption
||
*Use with caution in patients >60yo
*Previous history of HIT
||
*Avoid in CAD and in severe renal impairment
||
*Avoid in hepatic disease (Child-Pugh Class B/C)
||
*Avoid in severe hepatic disease and renal impairment
||
*Temporary hypercoagulable state for approx 5 days
|-
| '''Comments'''
||
*Dose adjustments may be necessary in obese patients
||
*Check PTT after 6hr; adjust infusion to maintain PTT at 1.5-2.5x control
||
||
*Consider interactions with CYP3A4 inhibitors (e.g. -azoles)
||
*Consider interactions with CYP3A4 inhibitors
||
*INR target 2.5
*Consider many drug-drug interactions with CYP450 inhibitors or inducers
|}
 
*Duration
**3-6 mo, if time limited risk factor (post-op, trauma, estrogen use)  
**6 mo to life, if idiopathic etiology or recurrent
 
===Subsegmental PE===
*Evaluate for proximal DVT in legs with ultrasound
**If low risk for recurrent VTE: Clinical surveillance recommended over anticoagulation ([[EBQ:Evidence_Levels|Level 2C]] evidence)<ref>Kearon, Clive, et al. "Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report." Chest (2016).[[http://www.cercp.org/images/stories/recursos/articulos_docs_interes/guia_tto_antitrombotico_tv_2016.pdf fulltext]]</ref>
**If high risk for recurrent VTE: anticoagulation recommended over surveillance
 
===Catheter-directed Therapy for intermediate-risk (submassive) PE<ref>Kucher N et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014 Jan 28;129(4):479-86. doi: 10.1161/circulationha.113.005544. Epub 2013 Nov 13</ref>===
*Includes catheter-directed thrombolysis and mechanical thrombus removal without thrombolysis
*Still no large prospective cohort or randomized trial evaluating CDT, so limited evidence recommendations from ACCP 2016 are weak
**Primary outcome measure in study of 59 patients was improved RV function at 24 hours, but not mortality
*Given broad clinical spectrum of intermediate-risk PE, CDT can be considered in a subset of patients with following characteristics:
**Intermediate-risk PE with more severe degree of RV dysfunction and positive biomarkers
**Intermediate-risk PE with severe hypoxemia
**High-risk (massive) PE with contraindications to systemic thrombolysis
*Complications include major access site bleeding, significant arrhythmias, pulmonary artery dissection, tamponade, worsening hemodynamics


===Thrombolysis===
===Thrombolysis===
Line 170: Line 245:
==Disposition==
==Disposition==
*Patients with significant clot burden generally require admission for anticoagulation
*Patients with significant clot burden generally require admission for anticoagulation
*Consider discharge in low risk patients with peripheral PE<ref>Vinson DR, Zehtabchi S, Yealy DM. Can selected patients with newly diagnosed pulmonary embolism be safely treated without hospitalization? A systematic review. Ann Emerg Med. 2012; 60:651-662.</ref>
*Consider discharge in low risk patients with peripheral PE <ref>Vinson DR, Zehtabchi S, Yealy DM. Can selected patients with newly diagnosed pulmonary embolism be safely treated without hospitalization? A systematic review. Ann Emerg Med. 2012; 60:651-662.</ref>  
*Risk stratify which patients can be discharged using HESTIA<ref>Zondag et al. Hestia criteria can discriminate high- from low-risk patients with pulmonary embolism. European Respiratory Journal. 2013; 41:588-592.</ref>, sPESI, or PESI scores<ref>Maughan et al. Outpatient Treatment of Low‐risk Pulmonary Embolism in the Era of Direct Oral Anticoagulants: A Systematic Review Academic Emergency Medicine 2021; 28: 226– 239. https://doi.org/10.1111/acem.14108</ref>.


==Prognosis==
==Prognosis==
Line 233: Line 309:


==External Links==
==External Links==
*[https://www.acep.org/patient-care/clinical-policies/acute-venous-thromboembolic-disease/ ACEP Clinical Policy: Acute Venous Thromboembolic Disease (Feb 2018)]
*[http://www.mdcalc.com/wells-criteria-for-pulmonary-embolism-pe/ MDCalc - Well's Criteria for Pulmonary Embolism]
*[http://www.mdcalc.com/wells-criteria-for-pulmonary-embolism-pe/ MDCalc - Well's Criteria for Pulmonary Embolism]
*[http://www.mdcalc.com/perc-rule-for-pulmonary-embolism/ MDCalc - PERC Rule for Pulmonary Embolism]
*[http://www.mdcalc.com/perc-rule-for-pulmonary-embolism/ MDCalc - PERC Rule for Pulmonary Embolism]
*[http://www.mdcalc.com/geneva-score-revised-for-pulmonary-embolism/ MDCalc - Geneva Score for Pulmonary Embolism]
*[http://www.mdcalc.com/geneva-score-revised-for-pulmonary-embolism/ MDCalc - Geneva Score for Pulmonary Embolism]
*[http://www.mdcalc.com/pulmonary-embolism-severity-index-pesi/  MDCalc - PESI - Pulmonary Embolism Severity Index]
*[http://www.mdcalc.com/pulmonary-embolism-severity-index-pesi/  MDCalc - PESI - Pulmonary Embolism Severity Index]
*[https://www.mdcalc.com/hestia-criteria-outpatient-pulmonary-embolism-treatment#evidence/ MDCalc - Hestia Criteria for Pulmonary Embolism]
*[https://www.mdcalc.com/has-bled-score-major-bleeding-risk/ MDCalc - HAS-BLED Score for major bleeding risk]


==References==
==References==

Revision as of 00:45, 3 September 2021

See pulmonary embolism in pregnancy for pregnancy specific information.[1]

Background

Clinical Spectrum of Venous thromboembolism

Only 40% of ambulatory ED patients with PE have concomitant DVT[2][3]

Pulmonary Embolism Categorization[4]

Massive: High-risk

Hemodynamically unstable with symptoms of shock

  • ACCP 2016 CHEST Guidelines: Sustained hypotension ONLY criteria (systolic BP <90 for at least 15min or requiring inotropic support)
  • Previous definitions (e.g. AHA 2011) include cardiac arrest/pulselessness or persistent profound bradycardia (HR <40 with signs of shock)

Submassive: Intermediate-risk

Right ventricular dysfunction (RVD) and/or myocardial necrosis in the absence of persistent hypotension or shock (SBP >90)[5]

  • RV dysfunction
    • RV dilation or dysfunction on TTE
      • "D Sign" on bedside echo (LV takes on a "D" shape due to RV dilation)
    • RV dysfunction on CT defined as RV/LV ratio >0.9[6]
    • Elevation of BNP (>90)
    • ECG findings of right heart strain (see diagnosis below)
  • Myocardial necrosis: Troponin I >0.4

Non-Massive: Low-risk

No hemodynamic compromise and no RV strain

Sub-Segmental

  • Limited to the subsegmental pulmonary arteries

Epidemiology

  • The best estimates indicate that 350,000 to 600,000 Americans each year suffer from DVT and PE[7]
  • Survival[8]
    • PE is the 3rd leading cause of cardiovascular morbidity and mortality
    • At least 100,000 deaths per year may be directly or indirectly related to DVT and PE
    • For almost one quarter of PE patients, the initial clinical presentation is sudden death
    • PE is an independent predictor of reduced survival for ≤3 months
    • One of the leading causes of out-of-hospital, non-trauma related sudden deaths [9]

Clinical Features

Symptoms

According to the PIOPED II study, these are the most common presenting signs[10]

Signs

  • Tachypnea (54%)
  • Calf or thigh swelling, erythema, edema, tenderness, palpable cord (47%)
  • Tachycardia (24%)
  • Rales (18%)
  • Decreased breath sounds (17%)
  • Accentuated pulmonic component of the second heart sound (15%)
  • JVD (14%)
  • Fever (3%)

Differential Diagnosis

Chest pain

Critical

Emergent

Nonemergent

Acute dyspnea

Emergent

Non-Emergent

Workup

Assessing Pretest Probability

  • Objective criteria (Geneva, Wells, etc.) is equal to gestalt in assessing pre-test probability[11] (ACEP Level B)
  • Initial Wells study and prospective validation [12] used a three tier system (low 0-1, intermediate 2-6, high >6) to establish pretest probability with a small sample size
  • The larger Christopher Study group used a larger sample size to derive the simplified dichotomized/two tier model below[13]

Wells Criteria

Clinical Features Points
Symptoms of DVT (leg swelling and pain with palpation) 3.0
PE as likely as or more likely than an alternative diagnosis 3.0
HR >100 bpm 1.5
Immobilization for >3 consecutive days or surgery in the previous 4 weeks 1.5
Previous DVT or PE 1.5
Hemoptysis 1.0
Malignancy (receiving treatment, treatment stopped within 6 mon, palliative care) 1.0
Two Tier Wells Score
  • Score 0-4 = PE Unlikely (12.1% incidence of PE)
    • Check D-dimer
      • If D-dimer positive then obtain CTPA or V/Q scan
      • If D-dimer negative, no further workup needed (0.5% incidence of PE at 3 month follow up)
  • Score >4 = PE Likely (37.1% incidence of PE)
    • Obtain CT Pulmonary Angiography or V/Q Scan
  • New evidence suggests lower Wells Score with D-dimer <1000 ng/mL is effective at ruling out PE without imaging

Low-Probability Testing in the ED

  • PERC Rule negative, then no further workup[11] (ACEP Level B)
    • Avoid CT pulmonary angiography in low pretest probability patients that are either PERC rule negative or have a negative d-dimer (ACEP choosing wisely)
    • D-dimer NPV is 99.5%[14]
  • PERC Rule positive, then D-dimer (see Moderate-Probability Testing below)[11] (ACEP Level B)
    • Can also consider using Wells score as above to determine further testing

Adjusted D-Dimer to Higher Threshold

Less common risk factors

  • HIV (protein wasting nephropathy)
  • Nephrotic Syndrome
  • SLE with anti-cardiolipin Ab
  • Exogenous hormones (specifically estrogen)
  • homozygous Factor V Leiden
  • Antithrombin III deficiency
  • Protein C deficiency
  • Protein S deficiency
  • Hyperhomocysteinemia

Evaluate bleeding risk (HAS-BLED)

  • HAS-BLED score (developed to evaluate bleeding risk for anticoagulation in Afib) can also identify patients with acute VTE at high risk for bleeding complications within 6 months[16]
Risk Factor Point
Hypertension 1
Abnormal renal and/or hepatic function 1 point each
Stroke 1
Bleeding tendency/predisposition 1
Labile INR on warfarin 1
Elderly (age >65 years) 1
Drugs (aspirin or NSAIDs) and/or alcohol 1 point each
  • When applied to VTE patients on vitamin K-antagonists, NOT DOACs (in first 6 months of treatment):
    • Score 0-2 = 1.3% incidence of major bleeds
    • Score 3+ = 9.6% incidence of major bleeds
  • Other bleeding risk models include the RIETE score (validated in patients taking VKA or rivaroxaban) and VTE-BLEED score (validated in patients taking warfarin and edoxaban).

Initial Management While Awaiting Workup[17]

  • based on ACCP 2016 Guidelines
Clinical suspicion Management
Low Do not treat with anticoagulation while awaiting diagnostic test results
Medium Treat with parenteral anticoagulation if the results of diagnostic tests are expected to be delayed ≥ 4 hours
High Treat with parenteral anticoagulation while awaiting diagnostic test results

Diagnosis

A large pulmonary embolism at the bifurcation of the pulmonary artery (saddle embolism).

Definitive Diagnostic Imaging

  • CTA Chest if GFR >60
  • V/Q scan if GFR <60
    • Will be nondiagnostic if patient has effusion, pneumonia, or other airspace disease
  • If imaging negative, perform additional diagnostic testing (e.g. lower extremity Doppler US, V/Q scan, and/or traditional pulmonary angiogram) prior to exclusion of VTE[11] (ACEP Level C)
    • A negative d-dimer in combination with a negative CTA theoretically provides a post-test probability of VTE less than 1%

Other Possible Diagnostic Findings

D Sign[18]
Hampton's Hump
  • ECG (abnormal in 70% of PE [19] and associated with an adverse prognosis[20])
    • T-wave inversions (34%)[21]
      • Anterior/septal leads (V1-V4) and inferior leads[22]
    • T-wave flattening (30%)
    • Sinus Tachycardia (27%)
    • Right axis deviation (11%)
    • St-segment changes in V1-V4 (9%)
    • S1Q3TS RV strain pattern (4%)
    • New-onset atrial arrhythmias (e.g. atrial fibrillation)
    • New RBBB (complete or incomplete) [23]
    • QR pattern in V1
  • CXR (abnormal in 70%)
    • Atelectasis is most common (esp >24 hrs after onset of symptoms)
    • Pleural effusion
    • Hampton's Hump
    • Westermark's sign[24]
  • Formal transthoracic echo or bedside cardiac ultrasound
    • Can help diagnosis in equivocal cases
    • May see signs of right heart strain (bowing of septum into LV; Aka D Sign)
      • Right ventricular strain is associated with statistically significant worse outcome[25]
    • McConnel's sign (akinesis of RV base/free wall with sparing of apex)
    • Lateral right ventricular wall diameter of <5mm is suggestive of acute pulmonary hypertension while >5mm is suggestive of chronic pulmonary hypertension[26]
  • SPECT
    • Combination of noncontrast CT chest with V/Q scan
    • Avoidance of contrast for patients with renal injury
    • As sensitive as CTPA and more sensitive than planar V/Q scanning[27]

Management

Supportive care

  • Oxygen therapy (maintain SpO2 ≥90% unless otherwise indicated)
  • Hemodynamic support (e.g. IVF, pressors)
    • Consider gentle fluid challenge of 500ml normal saline bolus to improve cardiac index in select patients[28]
    • Experimental studies suggest that aggressive volume expansion provides little benefit and may worsen RV function in those with acutely elevated RV afterload and acutely increased pulmonary HTN[29]

Anticoagulation

  • Always consider bleeding risk when determining risks/benefits of initiating anticoagulation
  • Treatment options include any of the following anticoagulations which are indicated for all patients with confirmed PE or high clinical suspicion (do not wait for imaging).
Name LMWH SC Unfractionated Heparin Dabigatran Rivaroxaban Apixaban Coumadin
Initial Dose
  • 80 units/kg bolus; then 18 units/kg/hr continuous infusion
  • Parenteral anticoagulation for 5-10 days; then 150mg twice daily
  • 15mg twice daily for 3 weeks, then 20mg once daily
  • 10mg twice daily for 1 week, then 5mg twice daily
  • Cannot be administered alone for acute PE. Usual starting dose 5mg PO
Benefits
  • 1st line for most hemodynamically stable patients
  • Preferred in those with cancer, liver disease, coagulopathy, pregnancy
  • Short half-life
  • Preferred if rapid reversal is needed (e.g. considering thrombolytics or with bleeding risk/trauma)
  • No need for renal dosing
  • Noninferior to warfarin in reducing DVT and PE [30]
  • Preferred if parenteral therapy to be avoided
  • Associated with less bleeding, particularly in elderly patients and those with moderate renal impairment compared to standard treatments [31]
  • Preferred if parenteral therapy to be avoided or if history of GI bleeding
  • Studies show 16% reduction in VTE related death compared to standard therapy [32]
  • Preferred in renal disease, history of poor compliance, or history of GI bleed
Contraindications
  • Severe renal impairment (CrCl <30 mL/min)
  • Patients with morbid obesity or anasarca may have poor absorption
  • Use with caution in patients >60yo
  • Previous history of HIT
  • Avoid in CAD and in severe renal impairment
  • Avoid in hepatic disease (Child-Pugh Class B/C)
  • Avoid in severe hepatic disease and renal impairment
  • Temporary hypercoagulable state for approx 5 days
Comments
  • Dose adjustments may be necessary in obese patients
  • Check PTT after 6hr; adjust infusion to maintain PTT at 1.5-2.5x control
  • Consider interactions with CYP3A4 inhibitors (e.g. -azoles)
  • Consider interactions with CYP3A4 inhibitors
  • INR target 2.5
  • Consider many drug-drug interactions with CYP450 inhibitors or inducers
  • Duration
    • 3-6 mo, if time limited risk factor (post-op, trauma, estrogen use)
    • 6 mo to life, if idiopathic etiology or recurrent

Subsegmental PE

  • Evaluate for proximal DVT in legs with ultrasound
    • If low risk for recurrent VTE: Clinical surveillance recommended over anticoagulation (Level 2C evidence)[33]
    • If high risk for recurrent VTE: anticoagulation recommended over surveillance

Catheter-directed Therapy for intermediate-risk (submassive) PE[34]

  • Includes catheter-directed thrombolysis and mechanical thrombus removal without thrombolysis
  • Still no large prospective cohort or randomized trial evaluating CDT, so limited evidence recommendations from ACCP 2016 are weak
    • Primary outcome measure in study of 59 patients was improved RV function at 24 hours, but not mortality
  • Given broad clinical spectrum of intermediate-risk PE, CDT can be considered in a subset of patients with following characteristics:
    • Intermediate-risk PE with more severe degree of RV dysfunction and positive biomarkers
    • Intermediate-risk PE with severe hypoxemia
    • High-risk (massive) PE with contraindications to systemic thrombolysis
  • Complications include major access site bleeding, significant arrhythmias, pulmonary artery dissection, tamponade, worsening hemodynamics

Thrombolysis

IVC Filter

  • Indications
    • anticoagulation contraindicated in patient with PE
    • failure to attain adequate anticoagulation during treatment

Disposition

  • Patients with significant clot burden generally require admission for anticoagulation
  • Consider discharge in low risk patients with peripheral PE [35]
  • Risk stratify which patients can be discharged using HESTIA[36], sPESI, or PESI scores[37].

Prognosis

The Pulmonary Embolism Severity Index (PESI)[38]

  • PE patients with PESI class I or II seem safe to manage as outpatients.
Prognosis Variable Points Assigned
Demographics
Age +Age in years
Male +10
Comorbid Conditions
Cancer +30
Heart Failure +10
Chronic Lung Diseae +10
Clincal Findings
Pulse >110 b/min +20
sBP < 100 +30
RR > 30 +20
Temp <36 C +20
AMS +60
Art O2 Saturation <90% +20
Risk Class 30-Day Mortality Total Point Score
I 1.60% <65
II 3.50% 66-85
III 7.10% 86-105
IV 11.40% 106-125
V 23.90% >125

See Also

Thrombolytics for pulmonary embolism

External Links

References

  1. D-Dimer Concentrations in Normal Pregnancy: New Diagnostic Thresholds Are Needed. Kline et all. Clinical Chemistry May 2005 vol. 51 no. 5 825-829 http://www.clinchem.org/content/51/5/825.long
  2. Righini M, Le GG, Aujesky D, et al. Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial. Lancet. 2008; 371(9621):1343-1352.
  3. Daniel KR, Jackson RE, Kline JA. Utility of the lower extremity venous ultrasound in the diagnosis and exclusion of pulmonary embolism in outpatients. Ann Emerg Med. 2000; 35(6):547-554.
  4. Jaff MR et al. Management of massive and submassive pulmonary embolism, ileofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011 Apr 26;123(16):1788-830. doi: 10.1161/CIR.0b013e318214914f. Epub 2011 Mar 21
  5. Martin C et al. Systemic thrombolysis for pulmonary embolism: a review. P T. 2016 Dec; 41(12):770-775
  6. Becattini C et al. Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test. Eur Heart J. 2011 Jul;32(13):1657-63. doi: 10.1093/eurheartj/ehr108. Epub 2011 Apr 18.
  7. Mozaffarien D et al. Heart disease and stroke statistics - 2015 report from the American Heart Association. Circulation. 2015;131:d29-e322
  8. U. S. Department of Health and Human Services. www.ncbi.nlm.nih.gov/blooks/NBK44178. The surgeon general's call to prevent deep vein thrombosis and pulmonary embolism. 2008
  9. Tintinalli, J. E. (2016). Venous Thromboembolism In J.E. Tintinali (8th Ed.), Tintinalli's Emergency Medicine: A Comprehensive Study Guide (pp. 389-390). New York, New York: McGraw Hill Education
  10. Stein PD et al. Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med. 2007;120(10):871.
  11. 11.0 11.1 11.2 11.3 ACEP Clinical Policy for Pulmonary Embolism full text
  12. Wolf SJ, et al. Prospective validation of Wells Criteria in the evaluation of patients with suspected pulmonary embolism. Ann Emerg Med. 2004 Nov;44(5):503-10
  13. van Belle A et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295(2):172-179. doi:10.1001/jama.295.2.172
  14. Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple
  15. Flex your D-dimer Taming of the SRU http://www.tamingthesru.com/blog/diagnostics/flex-your-d-dimer
  16. Kooiman J et al. The HAS-BLED score identifies patients with acute venous thromboembolism at high risk of major bleeding complications during the first six months of anticoagulant treatment. PLOS ONE. 2015 Apr 23;10(4):e0122520. doi: 10.1371/journal.pone.0122520. eCollection 2015.
  17. ACCP 9th Edition of the Antithrombotic Therapy Guidelines: Kearon C et al. Antithrombotic therapy for VTE disease. Chest. 2012;141:e419s – e494s. doi: 10.1378/chest.11-2301.
  18. http://www.thepocusatlas.com/right-ventricle
  19. Marchick, MR et al. 12-lead ECG findings of pulmonary hypertension occur more frequently in emergency department patients with pulmonary embolism than in patients without pulmonary embolism. Ann Emerg Med. 2010 Apr;55(4):331-5.
  20. Agarwal A et al. Acute management of pulmonary embolism. https://www.acc.org/latest-in-cardiology/articles/2017/10/23/12/12/acute-management-of-pulmonary-embolism. 2017
  21. Co I, Eilbert W, Chiganos T. New Electrocardiographic Changes in Patients Diagnosed with Pulmonary Embolism. J Emerg Med. 2017 Mar;52(3):280-285. doi: 10.1016/j.jemermed.2016.09.009. Epub 2016 Oct 11. PMID: 27742402.
  22. Kosuge M, Kimura K, Ishikawa T, et al. Electrocardiographic differentiation between acute pulmonary embolism and acute coronary syndromes on the basis of negative T waves. Am J Cardiol 2007; 99: 817–821
  23. Shopo, JD et al. Findings from 12-lead electrocardiography that predict circulatory shock in pulmonary embolism; a systematic review and meta-analysis. Acad Emerg Med. 2015 Oct;22(10):1127-37
  24. Sreenivasan S, Bennett S, Parfitt VJ. Images in cardiovascular medicine. Westermark's and Palla's signs in acute pulmonary embolism. Circulation. 2007 Feb 27;115(8):e211. full text
  25. Taylor, RA, et al. Point-of-care focused cardiac ultrasound for prediction of pulmonary embolism adverse outcomes. The Journal of Emergency Medicine. 2013; 45(3):392–399.
  26. Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010; 23(7):685-713.
  27. Lu Y, Lorenzoni A, Fox JJ, Rademaker J, Vander Els N, Grewal RK, Strauss HW, Schöder H. Noncontrast perfusion single-photon emission CT/CT scanning: a new test for the expedited, high-accuracy diagnosis of acute pulmonary embolism. Chest. 2014 May;145(5):1079-88
  28. Mercat A et al. Hemodynamic effects of fluid loading in acute massive pulmonary embolism. Crit Care Med. 1999 Mar;27(3):540-4
  29. Konstantinides SV et al. ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69 doi: 10.1093/eurheartj/ehu283
  30. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009; 361(24):2342-52. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014; 129(7):764-72.
  31. Hughes S. Rivaroxaban Stands up to standard anticoagulation for VTE treatment. Medscape Medical News. December 13, 2012.Buller HR, on behalf of the EINSTEIN Investigators. Oral rivaroxaban for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies [abstract 20]. Presented at: 54th Annual Meeting and Exposition of the American Society of Hematology; December 8, 2012; Atlanta, Ga.
  32. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013; 369(9):799-808.Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013; 368(8):699-708.
  33. Kearon, Clive, et al. "Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report." Chest (2016).[fulltext]
  34. Kucher N et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014 Jan 28;129(4):479-86. doi: 10.1161/circulationha.113.005544. Epub 2013 Nov 13
  35. Vinson DR, Zehtabchi S, Yealy DM. Can selected patients with newly diagnosed pulmonary embolism be safely treated without hospitalization? A systematic review. Ann Emerg Med. 2012; 60:651-662.
  36. Zondag et al. Hestia criteria can discriminate high- from low-risk patients with pulmonary embolism. European Respiratory Journal. 2013; 41:588-592.
  37. Maughan et al. Outpatient Treatment of Low‐risk Pulmonary Embolism in the Era of Direct Oral Anticoagulants: A Systematic Review Academic Emergency Medicine 2021; 28: 226– 239. https://doi.org/10.1111/acem.14108
  38. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med. 2005;172:1041-1046.