Outpatient PE treatment

Should we be treating “low-risk” patients with PE as outpatients? A look at the data.
Author: Jason Brown, Capt, USAF, MD (Resident Physician, University of Maryland) // Editor: Alex Koyfman, MD

Background
Venous thromboembolism (VTE) (deep vein thrombosis or pulmonary embolism) has an incidence of roughly 1 in 1,000 (1) with an incidence of PE with or without DVT of 2.3 per 10,000 (2).

One major factor to consider is that VTE is much more common in the elderly (80 (3)) and has a mortality highly associated with co-morbidities such as cancer and underlying cardiovascular disease.

In the distant past any diagnosis of DVT and/or PE would result in admission for heparin bridging to oral anticoagulation therapy. This was largely due to a fear that outpatient management would lead to an increase in fatal embolic or major bleeding events. However, there is a great amount of literature (4,5) that has established the safety of outpatient management of “low-risk” DVT; outpatient treatment has become standard of care for these patients (6).

“Low-risk” patients were those with no prior VTE, no PE, no prior heparin use, and no confounding co-morbidities (cancer, infection, stroke, etc).

So what about PE?
If outpatient management is standard of care for a select group of DVT patients, then can we treat PE as an outpatient?

Numerous studies have been published on the matter, which seem to suggest that, for a very select group of patients, outpatient treatment may be acceptable.

The problem is: how do you define “low-risk” for patients with pulmonary embolism?
Aujesky et al (8) sought to risk stratify patients using a pulmonary embolism severity score (PESI):

Differential Diagnosis

They then took all the patients in class I and II and excluded any patients with barriers to follow-up, renal failure, SBP <100mmHg, or those at high bleeding risk and assigned them to either inpatient or outpatient therapy. They showed that, in their 340 patients, there was no increased risk of major bleeding events or death at 90 days.

Vinson et al (9) attempted a meta-analysis including the Aujesky paper. They found that, with 777 patients, there was no associated thrombosis-related deaths in 6/7 studies and 5.6% in a study with a high proportion of cancer patients. Each paper used different criteria to determine “low-risk.”

Additionally, Zondag et al (10) performed a prospective cohort study in the Netherlands following 297 treated as outpatients for PE. This population was established using the Hestia criteria to determine eligibility. They found no increase in the risk of VTE recurrence, mortality, or major bleeding as compared to established inpatient rates.

Agterof et al (11) chose to define “low-risk” as, simply, those patients with PE and a low (<500 pg/mL) NT-proBNP. They had extensive exclusion criteria:

(i) hemodynamic or respiratory instability, defined as one of the following symptoms: collapse, systolic blood pressure 90%; (ii) illness unrelated to PE for which the patient would require hospitalization for more than 24 h; (iii) pain requiring intravenous analgesia; (iv) need for acute thrombolysis at presentation; (v) active bleeding or known hemorrhagic diathesis; (vi) pregnancy; (vii) in-hospital patients; (viii) likelihood of poor compliance; (ix) no support system at home; and (x) renal insufficiency, defined as a creatinine level >150 lmoL L)

They showed that, of the 351 patients enrolled, there were no deaths, major bleeding events, or recurrent VTE at 10 days or at 3 months.

So why aren’t we already doing this?
Otero et al (12) conducted a trial to answer that question. However, their study was stopped prematurely because of two, early (within 10 days of enrollment) deaths. One death was due to a GI hemorrhage in a 60-ish year old female and the other was a cardiac arrest in a 20-ish female secondary to a large RV thrombus. This created a short-term mortality of 2.8% (2/72) vs 0% (0/60) when comparing outpatient to inpatient therapy. The remainder of their data showed lower overall mortality (4.2% v 8.3%), lower recurrence rate (2.8% v 3.3%), and comparable rates of relevant bleeding (5.5% v 5%). The study used less-stringent inclusion and exclusion criteria than did Aujesky, Zondag, and Agterof.

The clinical variables used in the prediction rule were assigned the following scores: recent major bleeding episode and cancer with metastasis, 4 points each; creatinine levels of over 2 mg/dL, 3 points; cancer without metastasis and immobility due to a recent medical condition, 2 points each; and absence of surgery in the past 2 months and an age of over 60 years, 1 point each. (13)

The real answer is that we just don’t know how to define which patients are at low risk. The European Society of Cardiology (14) recently revised its 2014 guidelines to mention the conundrum which we face. They suggest using the PESI risk-stratification tool published by Aujesky et al to guide therapy. The American College of Cardiology last updated their guidelines in 2011 (14) and have proposed the definition of “low-risk” as, “acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE.”

Hopefully, there will be further investigation into the validation of some of the aforementioned stratification tools and studies will be able establish outpatient therapy as standard of care.
At this point, any outpatient treatment of acute PE is at the discretion of the provider. Keep in mind that the ACC quotes short-term mortality rates of up to 1%, even in “low-risk” patients by their loose definition.

So what’s the answer?
Well, it’s really up to you. Are you comfortable assuming a mortality rate of 0-2.8% in the first 10 days? Are you comfortable employing non-validated risk-stratification tools?
Right now you have to determine the amount of risk that you and the patient in front of you are comfortable with. Also, there has to be institutional buy-in from PCPs / specialists who will follow these patients in the outpatient setting. Hopefully, in the future, we will have answers to these questions.

References
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2. Anderson FA, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med. 1991;151(5):933-8.
3. White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107(23 Suppl 1):I4-8.
4. Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz J, Ginsberg J, Turpie AG, Demers C, Kovacs M. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677–81.
5. Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, Gallus AS, Simonneau G, Chesterman CH, Prins MH. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med1996; 334: 682–7.
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8. 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. Lancet. 2011;378(9785):41-8.
9. 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(5):651-662.e4.
10. Zondag W, Mos IC, Creemers-schild D, et al. Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost. 2011;9(8):1500-7.
11. Agterof MJ, Schutgens RE, Snijder RJ, Epping G, Peltenburg HG, Posthuma EF, Hardeman JA, van der Griend R, Koster T, Prins MH, Biesma DH. Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level. J Thromb Haemost 2010;8: 1235–41.
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14. Jaff MR, Mcmurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123(16):1788-830.