Outpatient Treatment of Pulmonary Embolism

Authors: Raul Hernandez, MD (EM Resident Physician, SUNY Downstate/Kings County Hospital) and Mark Silverberg, MD (EM Attending Physician and Associate Residency Director, SUNY Downstate/Kings County Hospital) // Edited by: Alex Koyfman, MD (@EMHighAK) & Justin Bright, MD (@JBright2021)

A 64 year-old woman with past medical history of diabetes mellitus type 2 that is well-controlled on insulin, hypertension, and asthma presents with 1 week of shortness of breath and cough productive of blood-tinged sputum. The shortness of breath became suddenly worse about an hour ago as she was walking into your emergency department for evaluation and at that time she had symptoms of pre-syncope. She is denying chest pain, palpitations, diaphoresis, nausea, recent travel, or surgery. The patient takes both a beta-blocker and a calcium channel blocker to control her hypertension. She took all of her medications this morning prior to presentation. The patient has no personal history of cancer and there is no significant family history. She denies the use of tobacco, alcohol, or any other drugs.

Triage vitals are notable for BP 160/90, pulse 60, respirations 20, oxygen saturation on room air 94%, and a temperature of 100.2. A subsequent rectal temperature is 99.8. A fingerstick glucose is 96 mg/dL. The patient is well-appearing, in no distress, and physical examination is largely unremarkable with the exception of bilateral lower extremity swelling with the right calf being of slightly larger girth than the left. ECG and chest x-ray are both normal. Labs are sent including D-dimer, BNP, and troponin. The only abnormal value is the D-dimer, which is 929 ng/mL. Ultrasound imaging reveals no clot in the lower extremities but due to the high suspicion for pulmonary embolism a CT angiography study of the pulmonary arteries is done revealing a small, subsegmental pulmonary embolism. You wonder if this patient needs to be admitted or if she can somehow be treated as an outpatient for her pulmonary embolism.

Background

The incidence of venous thromboembolism is estimated to have a combined rate of incident and recurrent cases in the United States as high as 900,000 cases per year. This includes pulmonary embolisms. [1] Up to 200,000 die from this disease. [2] When symptomatic disease is present, pulmonary embolism carries an 18-fold increased risk of death in the first 3 months and it is thought to be the cause of more deaths than either myocardial infarctions or strokes. [1] However, the increased use of anticoagulant therapy seems to have played an important role in decreasing mortality from PE over the past 2 decades. [3] Traditionally, this therapy had been administered in-patient, but there is a trend toward decreasing admissions by identifying patients who can be appropriately treated with anticoagulation on an outpatient basis. [4, 5]

A brief discussion on patient selection/risk stratification

The Policy Statement on the Evaluation and Management of Adult Emergency Department Patients with Suspected Pulmonary Embolism from the American College of Emergency Physicians (ACEP) was published in 2011. It evaluates several clinical decision rules (Geneva score, Wells score, Kline criteria, and Pisa model) that can be used to risk-stratify patients with suspected PE into low, intermediate, and high pre-test probability. [6] There is no overt rule preference stated by the guidelines. In fact, they state that clinical gestalt performs in a manner comparable to the clinical decision rules (CDRs) and can also be used to risk-stratify patients. A 2011 meta-analysis also looked at gestalt vs. CDRs (Wells and revised Geneva) and found comparable performance for risk-stratifying a subset of patients into a low pre-test probability group. [7] It should be noted that the accuracy of gestalt increases with increased clinical experience, although how significant this increase is has not been definitively determined. [8] Using gestalt to classify a patient as low-risk (<15% chance of a PE according to the creators of the rule) and then applying the PERC rule does yield a subgroup of patients in whom PE is very unlikely. [9, 10] The criticism leveled at the PERC rule by the ACEP Policy (not updated since 2011) is that at the time of their writing no study had prospectively applied the PERC rule to patients, limiting the strength of the recommendation they can give for using this system. Keep in mind that after applying any CDR, other decisions must still be made regarding which labs and/or imaging to choose to rule out PE.

Patients with acute PE

What if after you apply your preferred rule and run tests on your patient you find a PE? How do you decide if this patient is low-risk enough to send home on anticoagulation or if you must admit for inpatient management? You can apply another clinical decision rule like the Pulmonary Embolism Severity Index (PESI). The PESI and its simplified form the sPESI (the “s” stands for simplified) both use clinical criteria to predict the 30-day outcome for patients with PE. They have been externally validated to predict mortality and complications in patients newly diagnosed with PE. Neither can be used confidently in patients with renal failure or severe co-morbidities as these types of patients were excluded from the validation study. [11, 12] The European Society of Cardiology (ESC) in its 2014 ESC Guidelines On the Diagnosis and Management of Acute Pulmonary Embolism points to the sPESI for its simplicity of use as a method for identifying low-risk patients with a new diagnosis of PE and add troponin testing alongside it as a way to gain more prognostic value. [13] The role of echocardiography is somewhat up for debate. While the ESC feels there is too much heterogeneity of results from studies to be certain about its role, others feel it gives good prognostic value. [13, 14] Research is ongoing to determine how echocardiogram can help in the hemodynamically stable patient newly diagnosed with PE.

Closely linked to the issue of right ventricular function is brain-type natriuretic peptide (BNP). In one prospective study a cut-off of <500 pg/mL was used for N terminal pro-BNP. This was its sole measured lab value for determining outpatient therapy. However, it also used physiologic, social, and co-morbid conditions in its exclusion criteria. [15] Patients excluded on the basis of these criteria may have already been low risk. A meta-analysis also looked at BNP and NT pro-BNP levels for prognostic value and found that those with elevated levels were at higher risk for more complications. [16]

The RIETE score is another CDR that can be used once PE has been diagnosed and the subsequent risk of treatment is being weighed. It attempts to quantify the risk of major bleeding events after initiation of anticoagulation but due to validation issues its value is uncertain.  [17, 18]

Risks of outpatient therapy vs inpatient therapy

Several studies and meta-analyses have been devoted to determining the safety of home treatment of PE vs. inpatient treatment. [19-23] For the most part, results have been positive for outpatient therapy but one study in particular was stopped due to the death of two patients in the outpatient arm early in the study. It was stopped by the study’s data safety monitoring board and its steering committee after only 132 patients were recruited.  The overall mortality in this study for the outpatient arm was 4.2% as opposed to 8.3% in the inpatient arm. [21] Unfortunately, because it was stopped early conclusions cannot be made about the outcomes in the same way as a completed study. This latter study did not use validated instruments such as those discussed above to risk-stratify patients. Other studies have shown that outpatient management in appropriate patients is as effective as inpatient management of acute PE with a comparable risk of recurrence of DVT/PE and bleeding events (major and minor). A Cochrane Review [22] on the subject included only one study [24] with 339 patients. The primary results chosen by the review were short-term (30 day) and long-term (90 day) all-cause mortality. This study found no difference between inpatient and outpatient treatment. There was no statistically significant difference between the treatment groups in terms of short-term (RR 0.33, 95% CI 0.01 to 7.98, P = 0.49) or long-term (RR 0.98, 95% CI 0.06 to 15.58, P = 0.99) all-cause mortality. The reported death in this study was not due to PE. The most recent guidelines by the ESC and the American College of Chest Physicians (ACCP) do include outpatient management as a feasible option for treatment of DVT/PE. [4, 13]

Choice of anticoagulant

Early anticoagulation is the mainstay therapy for pulmonary embolism with the aim of helping to prevent mortality, worsening of the patient’s status, or recurrence. [13]

The Aujesky study [24] randomized patients to receive enoxaparin 1 mg/kg twice a day after discharge within 24 hours of randomization. Whether this was self-injection, caregiver administered, or visiting nurse administered was left up to the patient’s social circumstance. Inpatients were given the same treatment. This was combined with concurrent early initiation of oral anticoagulation with vitamin K antagonists (VKA). Though no specific regimen was imposed in terms of which VKA to use, how it should be initiated, or how long it should be taken (duration of 90 days was suggested for therapy). Only one outpatient (0.6%) compared to no inpatients developed recurrent DVT (primary outcome) and three outpatients (1.8%) compared to no inpatients had major bleeding events (secondary outcome) within 90 days. In addition, one patient in each treatment group died. Neither of these died from PE-related causes. The Hestia study [20], which only had an outpatient arm, had a very similar protocol. During a 3-month follow-up period, out of 297 patients 6 had recurrent VTE (2.0%, 95% CI 0.8-4.3). Of these 5 (1.7%) had recurrent PE. Three patients died (1.0%, 95% CI 0.2-2.9). None died from a fatal PE (primary outcome). Two patients had major bleeding events, with one of them being an intracranial bleed (secondary outcome). It should be noted that neither of these studies used the risk-stratification tools previously described. The Hestia study did use an 11 item list to determine patient risk-stratification.

The ESC guidelines looked at 6 different studies comparing novel oral anticoagulants (NOACs) including dabigatran, apixaban, rivaroxaban, and edoxaban to warfarin. They concluded that the NOACs are non-inferior to warfarin in terms of efficacy, and could perhaps be safer in terms of major bleeding events.  They make note that perhaps this apparent safety is due to patients in these trials being relatively young with few having cancer. They also ask practitioners to take into account factors such as cost of medication and social circumstances prior to deciding to treat on an outpatient basis. The ACCP guidelines give no specifications for what anticoagulation to use in the setting of PE.

Care must be taken when treating patients with compromised kidney function. Low-molecular weight heparin and fondaparinux have contraindications for patients in this group. Apixaban, rivaroxaban, and edoxaban all require modification of dosage based on creatinine clearance.

Benefits/cost analysis

Initial strategies for managing acute pulmonary embolism required hospitalization for bridging anticoagulation and regulation of the INR after initiation of oral anticoagulation with VKA. While patient safety is still the most important determinant of treatment strategy, decreasing cost has also become an aim of modern practice. In a recent study from the United States looking at costs related to inpatient care after diagnosis of PE the price for an admission lasting a mean length of 5 days was slightly greater than $37,000. This does not include other costs such as discharge to a skilled nursing facility.  [25] Presumptively, outpatient cost would be much less because the patient would be using fewer resources. Other risks associated with hospitalization may also be eliminated. For instance, the number of medication errors has been estimated to account for 19% of adverse events and over 7,000 deaths annually. [26] This represents a significant source of preventable risk to patients for whom outpatient management is an alternative.

Summary

Outpatient treatment of acute PE is still in its early stages. There is no certainty that it is definitely better than inpatient treatment but many promising studies show non-inferiority of both the outpatient setting and the medications prescribed to patients within this subset. If properly applied, CDRs can help stratify low-risk patients who may benefit from outpatient management. Choice of anticoagulant should be guided by cost, social circumstances, and appropriateness based on the patient’s co-morbidities (e.g., renal function).

References / Further Reading

1. Heit JA, Silverstein MD, Mohr DN, et al. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008;28(3):370-372.
2. Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. 2002;121:877-905.
3. Skaf E, Stein PD, Beemath A, Sanchez J, Olson RE. Fatal pulmonary embolism and stroke. Am J Cardiol. 2006 Jun 15;97(12):1776-7.
4. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College Of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):7S-47S.
5. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College Of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e419S-e494S.
6. Fesmire FM, Brown MD, Espinosa JA, et al. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med. 2011;57(6):628-652.
7. Lucassen W, Geersing G, Erkens PM, Reitsma JB, Moons KG, Büller H, et al. Clinical Decision Rules for Excluding Pulmonary Embolism: A Meta-analysis. Ann Intern Med. 2011;155:448-460.
8. Kabrhel C, Camargo CA Jr, Goldhaber SZ. Clinical gestalt and the diagnosis of pulmonary embolism: does experience matter? 2005;127(5):1627-1630.
9. Kline JA, Mitchell AMA, Kabrhel C, et al. Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism. J Thromb Haemost. 2004;2:1247-1255.
10. Wolf SJ, McCubbin TR, Nordenholz KE, et al. Assessment of the pulmonary embolism rule-out criteria for evaluation of suspected pulmonary embolism in the emergency department. Am J Emerg Med. 2008;26:181-185.
11. Donzé J, Le Gal G, Fine MJ, Roy PM, et al. Prospective validation of the Pulmonary Embolism Severity Index. A clinical prognostic model for pulmonary embolism. Thromb Haemost. 2008 Nov;100(5):943-8.
12. Jiménez D, Aujesky D, Moores L, et al.; RIETE Investigators. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med. 2010 Aug 9;170(15):1383-9.
13. Konstantinides SV, Torbicki A, Agnelli G, et al.; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033-69, 3069a-3069k.
14. Keller K, Beule J, Schulz A, Coldewey M, et al. Right ventricular dysfunction in hemodynamically stable patients with acute pulmonary embolism. Thromb Res. 2014 Apr;133(4):555-9.
15. Agterof MJ, Schutgens RE, Snijder RJ, et al. Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level. J Thromb Haemost. 2010 Jun;8(6):1235-41.
16. Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med. 2008 Aug 15;178(4):425-30.
17. Scherz N, Méan M, Limacher A, et al. Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism. J Thromb Haemost. 2013 Mar;11(3):435-43.
18. Ruíz-Giménez N, Suárez C, González R, et al.; RIETE Investigators. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost. 2008 Jul;100(1):26-31.
19. 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 Nov;60(5):651-662.e4. doi: 10.1016/j.annemergmed.2012.05.041.
20. Zondag W, Mos IC, Creemers-Schild D, et al.; Hestia Study Investigators. Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost. 2011 Aug;9(8):1500-7.
21. Zondag W, Kooiman J, Klok FA, Dekkers OM, Huisman MV. Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta-analysis. Eur Respir J. 2013 Jul;42(1):134-44.
22. Otero R, Uresandi F, Jiménez D, et al. Home treatment in pulmonary embolism. Thromb Res. 2010 Jul;126(1):e1-5.
23. Yoo HH, Queluz TH, El Dib R. Outpatient versus inpatient treatment for acute pulmonary embolism. Cochrane Database Syst Rev. 2014 Nov 20;11:CD010019.
24. Aujesky D, Roy PM, Verschuren F, et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. 2011 Jul 2;378(9785):41-8.
25. LaMori JC, Shoheiber O, Mody SH, Bookhart BK. Inpatient resource use and cost burden of deep vein thrombosis and pulmonary embolism in the United States. Clin  2015 Jan 1;37(1):62-70.
26. Kruer RM, Jarrell AS, Latif A. Reducing medication errors in critical care: a multimodal approach. Clinical Pharmacology : Advances and Applications. 2014;6:117-126. doi:10.2147/CPAA.S48530.
27. http://www.ncbi.nlm.nih.gov/pubmed/25315880