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Can Selected Patients With Newly Diagnosed Pulmonary Embolism Be Safely Treated Without Hospitalization? A Systematic Review

      Study objective

      Omitting inpatient therapy for emergency department patients with newly diagnosed pulmonary embolism occurs infrequently in the United States. We seek to describe the safety of initial outpatient management of these patients and their demographics, comorbidities, risk stratification, treatment, and outcomes.

      Methods

      We identified studies from searches of MEDLINE, EMBASE, and other databases from inception through March 22, 2012. We supplemented this with a search of conference proceedings and consultation with experts. We selected prospective studies of adults with acute, symptomatic, objectively confirmed pulmonary embolism who were discharged home without hospitalization. All contributing studies explicitly defined inclusion and exclusion criteria plus objectively confirmed outcome measures: recurrent thromboembolism, major hemorrhage, and mortality. Two investigators independently identified eligible studies and extracted data. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to assess study quality.

      Results

      From 2,286 screened titles/abstracts, we selected 8 studies with a total of 777 patients. Seven observational studies were rated low in quality. The one randomized controlled trial was higher in quality, used stricter inclusion criteria, and found that 90-day outcomes for outpatient management were not inferior to inpatient care. Among the 7 studies that reported 90-day outcome measures, the overall incidence of venous thromboembolic–related and hemorrhage-related mortality was very low: 0 of 741 (upper 95% confidence limit 0.62%).

      Conclusion

      The data on exclusive outpatient management of acute symptomatic pulmonary embolism are limited, but the existing evidence supports the feasibility and safety of this approach in carefully selected low-risk patients.

      Introduction

      Patients with acute deep venous thrombosis and pulmonary embolism have traditionally been treated initially with parenteral anticoagulation in the hospital. The advent of low-molecular-weight heparin transferred much of early deep venous thrombosis care to an outpatient setting.
      • Koopman M.M.
      • Prandoni P.
      • Piovella F.
      • et al.
      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.
      • Levine M.
      • Gent M.
      • Hirsh J.
      • et al.
      A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.
      • Grau E.
      • Tenias J.M.
      • Real E.
      • et al.
      Home treatment of deep venous thrombosis with low molecular weight heparin: long-term incidence of recurrent venous thromboembolism.
      • Vinson D.R.
      • Berman D.A.
      Outpatient treatment of deep venous thrombosis: a clinical care pathway managed by the emergency department.
      Although a similar site-of-treatment shift for select patients with pulmonary embolism has been recommended by several professional societies,
      British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group
      British Thoracic Society guidelines for the management of suspected acute pulmonary embolism.
      • Snow V.
      • Qaseem A.
      • Barry P.
      • et al.
      Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians.
      • Torbicki A.
      • Perrier A.
      • Konstantinides S.
      • et al.
      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).
      • Kearon C.
      • Akl E.A.
      • Comerota A.J.
      • 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.
      outpatient pulmonary embolism management is uncommon. Hindering acceptance of this change in practice is a lack of consensus about how to identify emergency department (ED) patients who are candidates for home treatment, along with concerns about patient safety.
      • Aujesky D.
      • Mazzolai L.
      • Hugli O.
      • et al.
      Outpatient treatment of pulmonary embolism.
      What is already known on this topic
      In some locations, not all patients with pulmonary embolism are hospitalized.
      What question this study addressed
      What is the safety of outpatient treatment for pulmonary embolism?
      What this study adds to our knowledge
      In this systematic review, 7 studies reported 90-day outcomes, which included 13 recurrences of thromboembolism, 3 major bleeding events, and 0 related deaths among 741 outpatients.
      How this is relevant to clinical practice
      This study suggests that safe outpatient treatment for carefully selected patients with pulmonary embolism may be possible.
      Emergency physicians provide care for most patients presenting with pulmonary embolism acquired outside the hospital and play a central role in choosing the initial management strategy. We sought to examine the evidence about the safety of exclusive ambulatory management for patients with acute symptomatic pulmonary embolism.

      Materials and Methods

       Selection of Participants

      We designed our review to answer the following research question: Can selected outpatients with newly diagnosed pulmonary embolism be treated safely and effectively without hospitalization? Previous reviews on overlapping questions exist,
      • Janjua M.
      • Badshah A.
      • Matta F.
      • et al.
      Treatment of acute pulmonary embolism as outpatients or following early discharge A systematic review.
      • Squizzato A.
      • Galli M.
      • Dentali F.
      • et al.
      Outpatient treatment and early discharge of symptomatic pulmonary embolism: a systematic review.
      but our approach differs in 3 ways.
      First, our patient population is restricted to those without hospitalization, excepting a period of observation (usually <24 hours) in the ED. We did not examine studies of shortened inpatient stay followed by early discharge.
      • Davies C.W.
      • Wimperis J.
      • Green E.S.
      • et al.
      Early discharge of patients with pulmonary embolism: a two-phase observational study.
      • Otero R.
      • Uresandi F.
      • Jimenez D.
      • et al.
      Home treatment in pulmonary embolism.
      By reviewing the initial site-of-treatment options available for outpatients with newly diagnosed pulmonary embolism, we focus on a clinical question highly relevant to emergency physicians.
      Second, unlike authors of previous reviews, we confined our search to studies that enrolled patients prospectively, excluding studies that used a retrospective assembly.
      • Ong B.S.
      • Karr M.A.
      • Chan D.K.
      • et al.
      Management of pulmonary embolism in the home.
      • Dager W.E.
      • King J.H.
      • Branch J.M.
      • et al.
      Tinzaparin in outpatients with pulmonary embolism or deep vein thrombosis.
      • Lui B.
      • Tran A.
      • Montalto M.
      Treatment of patients with pulmonary embolism entirely in Hospital in the Home.
      • Erkens P.M.
      • Gandara E.
      • Wells P.
      • et al.
      Safety of outpatient treatment in acute pulmonary embolism.
      • Kovacs M.J.
      • Hawel J.D.
      • Rekman J.F.
      • et al.
      Ambulatory management of pulmonary embolism: a pragmatic evaluation.
      This limits our review to studies of higher quality.
      Third, several large observational studies and a randomized controlled trial of outpatient pulmonary embolism management have been published since 2008, when earlier reviews ended their search.
      • Janjua M.
      • Badshah A.
      • Matta F.
      • et al.
      Treatment of acute pulmonary embolism as outpatients or following early discharge A systematic review.
      • Squizzato A.
      • Galli M.
      • Dentali F.
      • et al.
      Outpatient treatment and early discharge of symptomatic pulmonary embolism: a systematic review.
      We therefore have at our disposal a larger literature base to examine.
      We selected prospective studies for review if they contained the following components: (1) symptomatic patients with an acute presentation consistent with pulmonary embolism and with clear descriptions of demographics and comorbidities; (2) radiographic confirmation of the diagnosis; (3) explicit inclusion and exclusion criteria, including any risk assessment tool used to circumscribe patient eligibility; (4) specified exclusive outpatient management after the ED or clinic assessment; (5) a well-defined pharmacotherapy and follow-up treatment protocol; (6) objectively confirmed outcomes, including recurrent venous thromboembolism, major hemorrhage, and all-cause mortality within a specified duration (as defined by the original articles).
      We excluded studies with an atypical outpatient setting such as a hotel near the hospital. A hospital-in-home arrangement was not excluded because this involves home health care visits to the patient's residence for assistance with medication administration.
      • Shepperd S.
      • Doll H.
      • Angus R.M.
      • et al.
      Avoiding hospital admission through provision of hospital care at home: a systematic review and meta-analysis of individual patient data.
      We excluded studies that failed to define objective criteria for outcome measures or failed to report separately outcomes of their pulmonary embolism patients treated without hospitalization in cases of mixed cohorts: for example, a combined deep venous thrombosis and pulmonary embolism cohort or a combined inpatient-treatment and outpatient-treatment pulmonary embolism cohort. However, we contacted the authors of larger studies in this latter category (defined as those with 50 or more patients with pulmonary embolism treated entirely as outpatients) to inquire about the feasibility of obtaining outcome data for their outpatient subjects. If data were available for the outpatient pulmonary embolism population, the study was included in this review.

       Data Collection and Processing

      We performed a comprehensive computer-assisted search of the following biomedical databases from their inception through March 22, 2012: MEDLINE, EMBASE, SciVerse Scopus, Cumulative Index to Nursing and Allied Health Literature, Web of Knowledge, Cochrane Library, and the clinical trial registration Web site (http://www.clinicaltrials.gov). No time or language restrictions were used. The MEDLINE strategy is presented in Figure E1, available online at http://www.annemergmed.com. We searched the “related articles” option in MEDLINE and reviewed the references of the relevant articles by hand to identify additional citations. We examined the studies included in previous systematic reviews of related topics.
      • Janjua M.
      • Badshah A.
      • Matta F.
      • et al.
      Treatment of acute pulmonary embolism as outpatients or following early discharge A systematic review.
      • Squizzato A.
      • Galli M.
      • Dentali F.
      • et al.
      Outpatient treatment and early discharge of symptomatic pulmonary embolism: a systematic review.
      We also searched the conference proceedings of major emergency medicine organizations (Society for Academic Emergency Medicine, American College of Emergency Physicians, and Canadian Association of Emergency Physicians) for the previous 4 years (2008 to 2011) and performed MEDLINE searches of authors of identified abstracts to locate full articles not otherwise detected. Last, we consulted 3 experts in the field for additional references.
      Two investigators (D.R.V. and S.Z.) independently screened titles and abstracts of all references and then full texts of potentially eligible articles. We assessed interobserver agreement for study selection. The third investigator joined to resolve any disagreements (D.M.Y.).
      Two reviewers (D.R.V. and S.Z.) independently abstracted data from the selected studies, using a predesigned data collection instrument. Data elements included study characteristics (first author, publication year, study design, country, number of centers, site of outpatient care, number of pulmonary embolism patients [outpatient and total, if different]); patient characteristics (mean age, sex distribution); diagnostic criteria; use and description of risk-stratification instruments; outpatient ineligibility criteria; management variables; and outcomes (all-cause mortality, venous thromboembolic–related and hemorrhage-related mortality, nonfatal recurrent venous thromboembolism, and nonfatal major hemorrhage). If important variables were not explicitly stated in the study, we contacted the primary authors of the studies to gather the missing data.
      We assessed the quality of the included studies by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.
      • Guyatt G.H.
      • Oxman A.D.
      • Schunemann H.J.
      • et al.
      GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      In reporting our review, we adhered to the criteria proposed by the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

       Primary Data Analysis

      We calculated interobserver agreement for study selection with Cohen's κ. We calculated the 95% confidence intervals (CIs) with the modified Wald method. When the incidence of an event was 0 or the lower 95% confidence limit was less than 0.001, we reported only the upper 95% confidence limit.

      Results

      The flow diagram of our search is illustrated in the Figure. From the 2,286 titles and abstracts we screened, we identified 24 prospective studies that included patients with acute symptomatic pulmonary embolism initially treated without hospitalization. After full-text review, we identified 17 studies that met initial exclusion criteria: an atypical outpatient setting or arrangement, viz, a hotel (n=1)
      • Olsson C.G.
      • Bitzen U.
      • Olsson B.
      • et al.
      Outpatient tinzaparin therapy in pulmonary embolism quantified with ventilation/perfusion scintigraphy.
      ; and objective outcome measures not described or reported for the pulmonary embolism population treated entirely as outpatients (n=16).
      • Harrison L.
      • McGinnis J.
      • Crowther M.
      • et al.
      Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin.
      • Wells P.S.
      • Kovacs M.J.
      • Bormanis J.
      • et al.
      Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin: a comparison of patient self-injection with homecare injection.
      • Wilson SJA G.L.
      • Anderson D.R.
      Outpatient treatment of deep vein thrombosis and pulmonary embolism: a hospital-based program.
      • Savage K.J.
      • Wells P.S.
      • Schulz V.
      • et al.
      Outpatient use of low molecular weight heparin (Dalteparin) for the treatment of deep vein thrombosis of the upper extremity.
      • Bauld D.L.
      • Kovacs M.J.
      Dalteparin in emergency patients to prevent admission prior to investigation for venous thromboembolism.
      • Labas P.
      • Ohradka B.
      • Cambal M.
      Could deep vein thrombosis be safely treated at home?.
      • Heaton D.
      • Han D.Y.
      • Inder A.
      Outpatient treatment of community acquired venous thromboembolism—the Christchurch experience.
      • Ageno W.
      • Steidl L.
      • Marchesi C.
      • et al.
      Selecting patients for home treatment of deep vein thrombosis: the problem of cancer.
      • Arcelus J.I.
      • Caprini J.A.
      • Monreal M.
      • et al.
      The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients.
      • Kearon C.
      • Ginsberg J.S.
      • Julian J.A.
      • et al.
      Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism.
      • Santamaria A.
      • Juarez S.
      • Reche A.
      • et al.
      Low-molecular-weight heparin, bemiparin, in the outpatient treatment and secondary prophylaxis of venous thromboembolism in standard clinical practice: the ESFERA Study.
      • Hyers T.M.
      • Spyropoulos A.C.
      Community-based treatment of venous thromboembolism with a low-molecular-weight heparin and warfarin.
      • Zed P.J.
      • Filiatrault L.
      Clinical outcomes and patient satisfaction of a pharmacist-managed, emergency department–based outpatient treatment program for venous thromboembolic disease.
      • Hull R.D.
      • Pineo G.F.
      • Brant R.
      • et al.
      Home therapy of venous thrombosis with long-term LMWH versus usual care: patient satisfaction and post-thrombotic syndrome.
      • Hacobian M.
      • Shetty R.
      • Niles C.M.
      • et al.
      Once daily enoxaparin for outpatient treatment of acute venous thromboembolism: a case-control study.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      The majority of studies in this latter group contained a relatively small number of patients with pulmonary embolism treated without hospitalization—9 studies had 9 or fewer cases. Two of these studies had 50 or more patients with pulmonary embolism treated exclusively in an outpatient setting.
      • Kearon C.
      • Ginsberg J.S.
      • Julian J.A.
      • et al.
      Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      We contacted these authors and found that the data from Kearon et al
      • Kearon C.
      • Ginsberg J.S.
      • Julian J.A.
      • et al.
      Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism.
      were not accessible, but the results from Zondag et al
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      were available and included in this review. Characteristics of the 16 excluded studies are presented in Table E1, available online at http://www.annemergmed.com.
      Figure thumbnail gr1
      FigureFlow diagram of study selection process for systematic review.
      Interobserver agreement for study selection was 100% (κ 1.0; 95% CI 0.85 to 1.0).
      Eight studies were selected for systematic review.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      Seven of these were observational studies, including 6 prospective cohort studies that describe the outcome of pulmonary embolism patients treated entirely as outpatients
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      and 1 randomized controlled trial comparing 2 different outpatient treatment regimens.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      The latter trial is categorized as an observational study because it did not have an inpatient control arm. There was only 1 randomized trial that compared outpatient with inpatient care for patients with acute symptomatic pulmonary embolism
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      (Table 1).
      Table 1Characteristics of selected prospective studies of patients with acute, symptomatic pulmonary embolism treated without hospitalization.
      First AuthorYearStudy DesignCountryCenters, n, Academic/CommunitySite of Treatment and DispositionPatients With PEPatient Demographics
      Total, n
      Total number may also include patients with PE treated as inpatients.
      Discharged Home, nMean Age, YearsSex, % Women
      Kovacs
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      2000Observational study with consecutive samplingCanada3 academicOutpatient thrombosis unit1088156.1NR
      Beer
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      2003Observational study with convenience samplingSwitzerland2 academicNR1054369.0
      Demographics reported only for a larger study population, not just for patients with PE treated as outpatients.
      NR
      Wells
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      2005RCT comparing 2 outpatient LMWH regimens in DVT and PE ptsCanada4 academicOutpatient thrombosis unit909057.8
      Demographics reported only for a larger study population, not just for patients with PE treated as outpatients.
      45.9
      Demographics reported only for a larger study population, not just for patients with PE treated as outpatients.
      Siragusa
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      2005Observational study with consecutive sampling of patients with cancerItaly1 academicOutpatient thrombosis unit583661.5
      Demographics reported only for a larger study population, not just for patients with PE treated as outpatients.
      47.3
      Demographics reported only for a larger study population, not just for patients with PE treated as outpatients.
      Rodríguez-Cerrillo
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      2009Observational study (sampling method unclear)Spain1 academicED613066.870.0
      Agterof
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      2010Observational study of patients with NT-proBNP <500 pg/mLNetherlands5 academicED152
      Includes 47 patients who were hospitalized for a period of 6 to 24 hours for undisclosed reasons.
      10553.4
      Demographics reported only for a larger study population, not just for patients with PE treated as outpatients.
      51.3
      Demographics reported only for a larger study population, not just for patients with PE treated as outpatients.
      Zondag
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      2011Observational study with consecutive samplingNetherlands12 academic and communityED297
      Includes 68 patients who were hospitalized for less than 24 hours, mainly because CT scanning was not available at night.
      22955.0
      Demographics reported only for a larger study population, not just for patients with PE treated as outpatients.
      42.0
      Demographics reported only for a larger study population, not just for patients with PE treated as outpatients.
      Aujesky
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      2011RCT comparing inpt/outpt site of care for PE pts designated low risk by the PESI
      This noninferiority study specified a noninferiority margin of 4%.
      Switzerland, France, Belgium, United States19 academicED317163
      The per-protocol outpatient group, by definition, was discharged home from the ED less than 24 hours after randomization.
      47.050.9
      NR, Not reported; RCT, randomized controlled trial; LMWH, low-molecular-weight heparin; DVT, deep venous thrombosis; PE, pulmonary embolism; ED, emergency department; PESI, Pulmonary Embolism Severity Index.
      low asterisk Total number may also include patients with PE treated as inpatients.
      Demographics reported only for a larger study population, not just for patients with PE treated as outpatients.
      Includes 47 patients who were hospitalized for a period of 6 to 24 hours for undisclosed reasons.
      § Includes 68 patients who were hospitalized for less than 24 hours, mainly because CT scanning was not available at night.
      This noninferiority study specified a noninferiority margin of 4%.
      The per-protocol outpatient group, by definition, was discharged home from the ED less than 24 hours after randomization.
      With all 8 studies combined, 777 adult patients (≥18 years) with newly diagnosed pulmonary embolism were treated without initial hospitalization. Age and sex distribution varied across the studies. The mean age of the outpatient population cannot be ascertained because most studies failed to report the independent ages of this subpopulation.
      The clinical treatment setting also varied (Table 1). Three studies operated with a model in which patients receiving a diagnosis of pulmonary embolism in either the ED or clinical setting were then transferred to a centralized outpatient thrombosis unit for initiation of treatment and disposition.
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      Siragusa et al
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      observed that their outpatients spent a mean of 3.1 hours in the thrombosis unit. The other 2 thrombosis unit studies did not report length of stay.
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      In 4 studies, patients were discharged home directly from the ED.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      The ED length of stay in the study by Aujesky et al
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      required ED care to be completed within 24 hours from the time of randomization to be designated as outpatient management. Mean time from ED presentation until randomization was 13.9 hours for the outpatient cohort. ED length of stay was not reported in the other 3 ED studies.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      The quality of evidence grades are very low, low, moderate, and high according to criteria advanced by the GRADE guidelines and adopted by the American College of Chest Physicians.
      • Guyatt G.H.
      • Oxman A.D.
      • Schunemann H.J.
      • et al.
      GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology.
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • et al.
      GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
      • Guyatt G.H.
      • Norris S.L.
      • Schulman S.
      • et al.
      Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      The limitations and quality assessment of the studies are described in Table 2. The significant heterogeneity between the study populations precluded outcome-level assessments.
      Table 2Quality assessment of the selected studies of outpatient pulmonary embolism management using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.
      See references 20 and 21.
      Observational StudiesLimitations and Quality Assessment
      Possible limitations of observational studies
      • 1. Failure to develop and apply appropriate eligibility criteria (inclusion of control population)
      • 2. Flawed measurement of exposure and outcome
      • 3. Failure to control confounders and to measure all known prognostic factors
      • 4. Imprecision of outcomes (ie, wide confidence intervals)
      • 5. Incomplete follow-up
      Existing limitationsOverall quality of evidence
      Kovacs
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      1, 3, 4Very low
      Beer
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      1, 3, 4Very low
      Wells
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      This study is a nonblinded randomized controlled trial comparing the efficacy and safety of 2 different types of low-molecular-weight heparin in outpatient treatment of deep venous thrombosis or pulmonary embolism. Because the study was designed to address a different research question and the group assignments were not based on treatment location (in- or outpatient), we assessed the quality of this trial as we would have an observational study.
      1, 3, 4Very low
      Siragusa
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      1, 3, 4
      Number lost to follow-up is not reported in the article itself, but the primary author states that none was lost to follow-up.
      Very low
      Rodríguez-Cerrillo
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      1, 3, 4Very low
      Agterof
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      1, 3, 4Very low
      Zondag
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      1, 2, 3Very low
      Randomized Controlled TrialsLimitations of Quality Assessment
      Possible limitations of randomized trials
      • 1. Lack of allocation concealment
      • 2. Lack of blinding
      • 3. Incomplete accounting of patients and outcome events
      • 4. Selective outcome reporting bias
      • 5. Other limitations (eg, early termination, use of unvalidated outcomes, and recruitment bias)
      Existing limitationsOverall quality of evidence
      Aujesky
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      1, 2Moderate
      low asterisk See references
      • Guyatt G.H.
      • Oxman A.D.
      • Schunemann H.J.
      • et al.
      GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology.
      and
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      .
      This study is a nonblinded randomized controlled trial comparing the efficacy and safety of 2 different types of low-molecular-weight heparin in outpatient treatment of deep venous thrombosis or pulmonary embolism. Because the study was designed to address a different research question and the group assignments were not based on treatment location (in- or outpatient), we assessed the quality of this trial as we would have an observational study.
      Number lost to follow-up is not reported in the article itself, but the primary author states that none was lost to follow-up.
      Objective confirmation of the diagnosis of pulmonary embolism was clear in all 8 studies, though 2 failed to describe precisely the radiographic examinations used.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      The remaining 6 studies provided various levels of description about the diagnostic criteria for each radiographic examination. Common to these 6 were the following imaging studies: spiral computed tomography (CT) pulmonary angiography, pulmonary angiography, and ventilation perfusion lung scintigraphy; none used magnetic resonance imaging. Four studies diagnosed pulmonary embolism in symptomatic patients with nonhigh (or nondiagnostic) lung scintigraphy if one of the following existed: high pretest probability for pulmonary embolism
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      or ultrasonographically diagnosed deep venous thrombosis.
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      Two studies also secured the diagnosis of pulmonary embolism without lung imaging if there was a high clinical suspicion of pulmonary embolism (by dyspnea or chest pain) combined with an objectively confirmed deep venous thrombosis.
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      The details of the studies' various diagnostic approaches are described in Table E2, available online at http://www.annemergmed.com.
      Three studies undertook explicit risk stratification with various instruments. Beer et al
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      used a prediction rule from Geneva University Hospital that includes 6 variables: cancer, heart failure, history of deep venous thrombosis, hypotension, hypoxemia (as measured by arterial blood gas), and concomitant deep venous thrombosis.
      • Wicki J.
      • Perrier A.
      • Perneger T.V.
      • et al.
      Predicting adverse outcome in patients with acute pulmonary embolism: a risk score.
      Agterof et al
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      used a single laboratory value, N-terminal pro b-type natriuretic peptide (NT-proBNP), to divide patients into low-risk (<500 pg/mL) and higher-risk categories (≥500 pg/mL). Aujesky et al
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      used the Pulmonary Embolism Severity Index, the most extensively studied of the current pulmonary embolism prognostic instruments. It is composed of 11 variables obtainable at the bedside, including demographics (age, sex), comorbidities (cancer, heart failure, chronic lung disease), and clinical characteristics (pulse, blood pressure, respiratory rate, temperature, mental status, oxygen saturation).
      • Aujesky D.
      • Obrosky D.S.
      • Stone R.A.
      • et al.
      Derivation and validation of a prognostic model for pulmonary embolism.
      In the 3 studies that used a risk-stratification tool to designate a low-risk population, each used additional social or medical conditions to preclude outpatient treatment.
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      The 5 studies that did not use a prognostic index used their set of outpatient ineligibility criteria as the sole basis of their initial site-of-care decision.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      Outpatient ineligibility criteria include the following categories: pulmonary embolism characteristics, patient symptoms, vital sign abnormalities, contraindications to anticoagulation, comorbidities, barriers to treatment adherence or follow-up, and patient preference (Table 3).
      Table 3Outpatient ineligibility criteria for patients with acute symptomatic pulmonary embolism.
      First Author
      Kovacs
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      Beer
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      Wells
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      Siragusa
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      Rodríguez-Cerrillo
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      Agterof
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      Zondag
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      Aujesky
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      Outpatient ineligibility criteria used to augment explicit risk stratification tool
      Factors
      PE characteristics
      Massive
      Received clot lysis or extraction therapy at presentation
      Diagnosis >23 h before enrollment
      Anticoagulation
      Use of heparinoid for >36 h
      Ongoing anticoagulant treatment
      International normalized ratio greater than or equal to 2.0.
      Symptoms
      Severe pain (often chest) requiring parenteral opioids
      Patients were excluded from outpatient management if more than 24 hours of parenteral analgesia were required.
      Vital signs
      Hemodynamic instability or hypotension
      This variable was not strictly an exclusion criterion, but it is incorporated into the prognostic model such that is was minimally represented or absent in the cohort.
      Tachycardia
      This variable was not strictly an exclusion criterion, but it is incorporated into the prognostic model such that is was minimally represented or absent in the cohort.
      Hypoxemia or oxygen requirement
      This variable was not strictly an exclusion criterion, but it is incorporated into the prognostic model such that is was minimally represented or absent in the cohort.
      Patients were excluded if more than 24 hours of supplemental oxygen was required to maintain saturation greater than 90%.
      Uncontrolled hypertension
      Contraindications to anticoagulation
      Active bleeding
      Acute anemia
      Thrombocytopenia
      Known bleeding disorder
      Renal insufficiency or failure
      Severe liver impairment
      Recent stroke
       Within 10 days
       Within 4 wk
      Recent gastrointestinal bleed (within 14 days)
      Recent operation (within 2 wk)
      High risk of major bleeding, not otherwise specified
      Heparin intolerance
      Allergy
      History of heparin-induced thrombocytopenia
      Comorbidities
      Other diagnosis requiring hospitalization
      Patients were excluded if they had a medical or social reason to be in the hospital for more than 24 hours.
      Heart failure
      This variable was not strictly an exclusion criterion, but it is incorporated into the prognostic model such that is was minimally represented or absent in the cohort.
      This variable was not strictly an exclusion criterion, but it is incorporated into the prognostic model such that is was minimally represented or absent in the cohort.
      Arrhythmia
      Pregnancy
      Extreme obesity
      Poor clinical condition related to concomitant medical disorders
      Life expectancy <3 mo
      Barriers to treatment adherence or follow-up
      Social issues (eg, lack of telephone, transport, support)
      Lack of around-the-clock caregiver
      Alcohol or illicit drug use
      Psychosis, dementia, or other psychiatric condition
      Homelessness or no fixed address
      Imprisonment
      Patient preference/consent
      low asterisk International normalized ratio greater than or equal to 2.0.
      Patients were excluded from outpatient management if more than 24 hours of parenteral analgesia were required.
      This variable was not strictly an exclusion criterion, but it is incorporated into the prognostic model such that is was minimally represented or absent in the cohort.
      § Patients were excluded if more than 24 hours of supplemental oxygen was required to maintain saturation greater than 90%.
      Patients were excluded if they had a medical or social reason to be in the hospital for more than 24 hours.
      Treatment included subcutaneous low-molecular-weight heparin for at least 5 days while awaiting an oral vitamin K antagonist, if prescribed, to reach therapeutic levels. In addition, short-term follow-up was common, including an arranged clinic appointment at 7 to 10 days, preceded in many cases by researcher-initiated telephone calls. One trial provided daily home health care visits.
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      All studies included some degree of patient or caregiver education on medication usage and the signs and symptoms requiring medical attention. Details of the pharmacotherapy and follow-up for each of the studies are described in Table E3, available online at http://www.annemergmed.com.
      All studies defined their outcome measures objectively and required confirmation of venous thromboembolic events, using explicit criteria. Four studies used an independent committee to adjudicate suspected outcomes.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      Major bleeding was defined according to standard definitions.
      • Levine M.
      • Gent M.
      • Hirsh J.
      • et al.
      A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.
      • Schulman S.
      • Kearon C.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
      Mortality is reported in 3 categories: overall, venous thromboembolic related, and hemorrhage related. Nonfatal events include venous thromboembolism recurrence and major bleeding. For the randomized controlled trial, outcomes for both the outpatient and inpatient groups are reported, along with the difference in percentages. No patients in any study were lost to follow-up.
      The incidence of adverse events was low (Table 4). Apart from one small study that did not report 90-day outcomes,
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      the remaining 7 studies with their combined 741 patients found no case (upper 95% confidence limit 0.62%) of venous thromboembolic–related or hemorrhage-related death at 90 days.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      Even if the 2 venous thromboembolic–related and hemorrhage-related deaths in the one study that reported only 180-day outcomes
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      had occurred within the first 90 days, the total maximal number of venous thromboembolic–related and hemorrhage-related deaths among all 777 patients would have been 2 (0.26%; upper 95% confidence limit 1.00%). Among the 7 studies that reported 90-day nonfatal recurrent venous thromboembolic events, the rate ranged from 0% to 6.2%. Among these same studies, the 90-day rate of nonfatal major hemorrhage ranged from 0% to 1.2%. Several studies also reported outcomes between 7 and 14 days,
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      a temporal horizon of interest to emergency physicians.
      • Kabrhel C.
      • Sacco W.
      • Liu S.
      • et al.
      Outcomes considered most important by emergency physicians when determining disposition of patients with pulmonary embolism.
      Table 4Outcomes of outpatients with pulmonary embolism treated without hospitalization.
      MortalityNonfatal Events
      First AuthorPatients nEndpoint, DaysOverall Mortality, n (%, 95% CI)
      If the incidence is 0, only the upper 95% confidence limit is presented in parentheses (which is technically a 97.5% CI).
      VTE-Related Mortality, n (%, 95% CI)Hemorrhage-Related Mortality, n (%, 95% CI)VTE Recurrence, n (%, 95% CI)Major Bleeding Event, n (%, 95% CI)
      Observational studies
      Kovacs
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      81904 (4.9, 1.6–12.4)0 (5.4)0 (5.4)5 (6.2, 2.3–14.0)1 (1.2, 0.01–7.3)
      Beer
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      43900 (9.8)0 (9.8)0 (9.8)1 (2.3, 0–13.2)0 (9.8)
      Wells
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      90903 (3.3, 0.7–9.8)0 (4.9)0 (4.9)2 (2.2, 0.1–8.2)0 (0, 0–4.9)
      Siragusa
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      3618011 (30.6, 17.9–47.0)2 (5.6, 0.6–19.1)
      The study did not report these results. They were obtained from the primary author.
      0 (11.5)
      The study did not report these results. They were obtained from the primary author.
      2 (5.6, 0.6–19.1)1 (2.8, 0.01–15.4)
      Rodríguez-Cerrillo
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      30900 (11.6)0 (11.6)0 (11.6)0 (11.6)0 (11.6)
      Agterof
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      105
      • 10
      • 90
      • 0 (4.2)
      • 0 (4.2)
      • 0 (4.2)
      • 0 (4.2)
      • 0 (4.2)
      • 0 (4.2)
      • 0 (4.2)
      • 0 (4.2)
      • 0 (4.2)
      • 0 (4.2)
      Zondag
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      229
      The study reported 7- and 90-day outcomes for 297 patients with PE, 68 of whom were hospitalized for diagnostic purposes less than 24 hours. The 90-day results for the 229 patients discharged home directly from the ED were obtained from the authors.
      902 (0.9, 0–3.3)0 (2.0)0 (2.0)4 (1.7, 0.5–4.6)
      These patients did not all have objective confirmation of their presumed recurrent venous thromboembolism. Of their total cohort of 297 patients, 6 had presumed recurrent venous thromboembolism, only 1 of whom underwent objective confirmation.
      0 (2.0)
      Randomized controlled trial
      Aujesky
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      Ninety-day outcomes are reported for the per-protocol groups. Fourteen-day outcomes are reported for the primary analysis groups, which include 8 patients in the outpatient group who were not strictly outpatients according to the authors' definition and 14 patients in the inpatient group who were not strictly inpatients according to the authors' definition.
       Outpatients
      • 171
      • 163
      • 14
      • 90
      • 0 (2.6)
      • 1 (0.6, 0.1–3.7)
      • 0 (2.6)
      • 0 (2.8)
      • 0 (2.6)
      • 0 (2.8)
      • 0 (2.6)
      • 1 (0.6, 0.1–3.7)
      • 2 (1.2, 0.1–4.4)
      • 2 (1.2, 0.1–4.6)
       Inpatients
      • 168
      • 154
      • 14
      • 90
      • 0 (2.7)
      • 1 (0.7, 0–4.0)
      • 0 (2.7)
      • 0 (2.9)
      • 0 (2.7)
      • 0 (2.9)
      • 0 (2.7)
      • 0 (2.9)
      • 0 (2.7)
      • 0 (2.9)
      VTE, Venous thromboembolism.
      low asterisk If the incidence is 0, only the upper 95% confidence limit is presented in parentheses (which is technically a 97.5% CI).
      The study did not report these results. They were obtained from the primary author.
      The study reported 7- and 90-day outcomes for 297 patients with PE, 68 of whom were hospitalized for diagnostic purposes less than 24 hours. The 90-day results for the 229 patients discharged home directly from the ED were obtained from the authors.
      § These patients did not all have objective confirmation of their presumed recurrent venous thromboembolism. Of their total cohort of 297 patients, 6 had presumed recurrent venous thromboembolism, only 1 of whom underwent objective confirmation.
      Ninety-day outcomes are reported for the per-protocol groups. Fourteen-day outcomes are reported for the primary analysis groups, which include 8 patients in the outpatient group who were not strictly outpatients according to the authors' definition and 14 patients in the inpatient group who were not strictly inpatients according to the authors' definition.
      Two studies measured patient satisfaction. Agterof et al
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      used the Patient Satisfaction Questionnaire 18, which is scored on a Likert scale from 0 (not satisfied) to 5 (very satisfied). The mean score on day 10 of patients with pulmonary embolism treated exclusively as outpatients was 3.80 (SD 0.97). In the randomized trial by Aujesky et al,
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      patient satisfaction did not differ between groups: 156 (92%) of 170 outpatients and 158 (95%) of 167 inpatients were satisfied or very satisfied with the medical care received (P=.39). Regarding site-of-care preferences, more from the inpatient control arm preferred home therapy than those in the experimental outpatient arm preferred inpatient care.

      Limitations

      This review is limited by the small number of randomized controlled studies available for inclusion. The observational nature of 7 of the 8 studies subjects the findings to significant risk of bias because of lack of controlling for numerous confounding factors. Nonetheless, we included these data to ensure we had the most complete information on safety, a critical factor in choosing outpatient care. The heterogeneity of patient inclusion/exclusion criteria prevented any formal meta-analysis of outcomes.
      The rate of adverse events might be higher than this literature reports if studies with more worrisome results failed to make it to press. We were unable to estimate the effect of publication bias on this literature because of the number and the nature of the studies available for review.
      • Guyatt G.H.
      • Oxman A.D.
      • Montori V.
      • et al.
      GRADE guidelines: 5. Rating the quality of evidence—publication bias.

      Discussion

      Changing common practice is difficult for a condition like acute pulmonary embolism, in which serious complications occur in a limited few.
      • Pollack C.V.
      • Schreiber D.
      • Goldhaber S.Z.
      • et al.
      Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry).
      Physicians often overestimate the risk of harm with novel treatment strategies or assume hospital-based care is necessarily safer than alternative arrangements. Identifying which subgroups of patients with any illness, acute pulmonary embolism included, can be treated well in a less costly and more comfortable setting is key to enhancing health care efficiency and patient satisfaction.
      Despite the design differences among the studies we reviewed, the overall rates of complications were low. Because of methodological limitations, the observational studies can report only absolute outcome rates, without the ability to compare rates with a similar inpatient cohort. We included these diverse studies to ensure that all potential safety data were assessed.
      The dissimilar eligibility criteria of the studies demonstrate how outcomes, especially all-cause mortality and venous thromboembolism recurrence, vary with patient selection. The highest rate of complications was found in the study of active cancer patients
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      (Table 4). The presence of cancer is known to increase the incidence of adverse events in patients being treated for pulmonary embolism,
      • Connolly G.C.
      • Khorana A.A.
      Risk stratification for cancer-associated venous thromboembolism.
      though outpatient pulmonary embolism management has still been undertaken successfully in this population.
      • Ageno W.
      • Steidl L.
      • Marchesi C.
      • et al.
      Selecting patients for home treatment of deep vein thrombosis: the problem of cancer.
      • Ageno W.
      • Grimwood R.
      • Limbiati S.
      • et al.
      Home-treatment of deep vein thrombosis in patients with cancer.
      However, measures of success and safety for cancer patients must be calibrated in light of their higher risks. The other observational studies had lower rates of adverse outcomes than the cancer study but also included fewer cancer patients (less than 20% of their total pulmonary embolism populations).
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      One study did not report the prevalence of cancer in their population.
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      Cancer prevalence may also have had a bearing on the low adverse event rates of the randomized trial.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      Aujesky et al
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      used a prognostic index to risk-stratify patients and then restrict outpatient management to those identified as low risk for short-term mortality. Because active cancer or a history of cancer was incorporated into the Pulmonary Embolism Severity Index, low-risk patients who were eligible for outpatient therapy had a very low prevalence of cancer (only 4/339; 1.2%), the lowest reported of all the studies reviewed. Age, another rough predictor of mortality, is also included in the Pulmonary Embolism Severity Index, which is why this randomized controlled population appeared to be the youngest of all 8 studies (Table 1).
      Because of its controlled design, the study by Aujesky at al
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      offers a distinct perspective on the safety of initial ambulatory management of patients with pulmonary embolism. Whereas the uncontrolled studies could report only absolute rates, the randomized trial allows one to determine whether outpatient therapy is roughly more or less safe and effective than inpatient management. If less safe, one then can estimate the incremental risk incurred by replacing traditional inpatient care with outpatient management. This more particular question yields a more focused answer. The noninferiority margin was specified a priori at 4%, meaning that if outpatient outcomes were not worse than the inpatient comparator by more than 4% (as measured by the upper limit of the 95% CI), then outpatient treatment could be considered noninferior to its counterpart. The outcomes between the groups were comparable and the upper 95% confidence limit for the differences in the per-protocol cohorts for 90-day mortality was very low (2.1%) (Table 4).
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      The study by Aujesky et al
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      is not the only trial to have randomized ED patients with acute pulmonary embolism to conventional inpatient care or to accelerated discharge. Although not included in our structured review, the study by Otero et al
      • Otero R.
      • Uresandi F.
      • Jimenez D.
      • et al.
      Home treatment in pulmonary embolism.
      used a noninferiority randomized design to assess the accuracy of a clinical prediction rule in identifying patients eligible for early hospital discharge. The study was stopped prematurely because of a higher-than-expected overall short-term mortality rate. In contrast to other studies, notably that by Aujesky et al,
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      these authors did not select low-risk patients with a validated tool, explaining in part the outcomes that drove the early termination.
      Early discharge was defined in the study by Otero et al
      • Otero R.
      • Uresandi F.
      • Jimenez D.
      • et al.
      Home treatment in pulmonary embolism.
      as discharge after 3 or 5 days of hospitalization. The duration from presentation to ED discharge in the study by Aujesky et al
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      was much shorter—less than 36 hours, though most patients went home from the ED within 24 hours. In hospitals with the appropriate facilities or services, ED patients who are likely to be kept longer than 8 hours but less than 24 hours and who meet specified criteria will often be transferred to a short-stay observation unit (or service).
      • Baugh C.W.
      • Venkatesh A.K.
      • Bohan J.S.
      Emergency department observation units: a clinical and financial benefit for hospitals.
      • Wiler J.L.
      • Ross M.A.
      • Ginde A.A.
      National study of emergency department observation services.
      A clinical decision unit may be ideally suited for selected low-risk patients with acute symptomatic pulmonary embolism for whom an 8- to 23-hour course of monitored observation ensures eligibility for outpatient management with careful follow-up.
      • Bledsoe J.
      • Hamilton D.
      • Bess E.
      • et al.
      Treatment of low-risk pulmonary embolism patients in a chest pain unit.
      Only 3 of our 8 studies used an explicit risk-stratification tool,
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      and these are but 3 of the various risk-assessment tools that exist to help guide clinicians in the management of outpatients with newly diagnosed pulmonary embolism.
      • Jimenez D.
      • Aujesky D.
      • Yusen R.D.
      Risk stratification of normotensive patients with acute symptomatic pulmonary embolism.
      • Geersing G.J.
      • Oudega R.
      • Hoes A.W.
      • et al.
      Managing pulmonary embolism using prognostic models: future concepts for primary care.
      Prognostic models are developed to provide objective estimates of outcome probabilities to complement clinical intuition and judgment.
      • Moons K.G.
      • Altman D.G.
      • Vergouwe Y.
      • et al.
      Prognosis and prognostic research: application and impact of prognostic models in clinical practice.
      • Moons K.G.
      • Kengne A.P.
      • Grobbee D.E.
      • et al.
      Risk prediction models: II. External validation, model updating, and impact assessment.
      The most rigorously studied validated risk-stratification tool to date is the Pulmonary Embolism Severity Index. Combined with outpatient ineligibility criteria, the Pulmonary Embolism Severity Index provides a reliable means of identifying low-risk patients who are candidates for exclusive ambulatory management.
      The outpatient management of carefully selected patients with pulmonary embolism has been more broadly implemented and studied in Europe and Canada than in the United States. In some Canadian tertiary care centers, approximately 50% of patients with acute symptomatic pulmonary embolism are treated entirely as outpatients.
      • Erkens P.M.
      • Gandara E.
      • Wells P.
      • et al.
      Safety of outpatient treatment in acute pulmonary embolism.
      • Kovacs M.J.
      • Hawel J.D.
      • Rekman J.F.
      • et al.
      Ambulatory management of pulmonary embolism: a pragmatic evaluation.
      • Baglin T.
      Fifty per cent of patients with pulmonary embolism can be treated as outpatients.
      In contrast, a recent large pulmonary embolism registry from 22 EDs in the United States
      • Pollack C.V.
      • Schreiber D.
      • Goldhaber S.Z.
      • et al.
      Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry).
      found that only 21 of 1,880 (1.1%) patients were discharged home from the ED without hospitalization. Several factors might contribute to this wide geographic variation in practice, including issues of health insurance compensation and malpractice litigation.
      Five studies incorporated patient preferences into their site-of-treatment decisions.
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      No study assessed in a structured fashion a priori patient knowledge or site-of-treatment preferences, an important part of implementing any care plan.
      • Hess E.P.
      • Knoedler M.A.
      • Shah N.D.
      • et al.
      The chest pain choice decision aid: a randomized trial.
      Both studies that measured satisfaction after care found high ratings for those treated exclusively as outpatients.
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      Ongoing advances in pharmacotherapy for venous thromboembolism may also facilitate the transition from inpatient to outpatient care. There are many oral direct factor inhibitors in development and in various stages of clinical trials.
      • Ansell J.
      • Askin D.
      New targets for anticoagulation and future perspectives.
      • Ansell J.
      Will the new target-specific oral anticoagulants improve the treatment of venous thromboembolism?.
      A recent noninferiority study suggested that monotherapy with an oral direct Xa inhibitor may be as effective and safe as the traditional combination of subcutaneous low-molecular-weight heparin and an oral vitamin K antagonist.
      • Buller H.R.
      • Prins M.H.
      • Lensin A.W.
      • et al.
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      It will be interesting to see what effect these new treatments have on site-of-care decisions for low-risk ED and clinic patients with pulmonary embolism.
      The next steps in evaluating the opportunities to shift to an exclusive outpatient treatment model for selected patients with acute symptomatic pulmonary embolism will revolve around the therapeutic options that are coming available, along with large-scale monitoring of outcomes in clinical care. Absent this type of phase 4 work, the risk and reward equation in daily practice cannot be fully defined.
      In summary, the current data suggest that exclusive outpatient management of carefully selected low-risk patients with acute symptomatic pulmonary embolism is feasible and appears to be safe, as measured by short-term mortality, recurrent venous thromboembolism, and major bleeding.
      The authors acknowledge with gratitude Ana M. Macias, MLIS, AHIP, and Amy C. Studer, RN, MSN, MSLIS, Health Sciences Library, Kaiser Permanente South Sacramento Medical Center, CA, for their assistance with the MEDLINE searches; Sergio Siragusa, MD, Cattedra di Ematologia, Università degli Studi di Palermo, Palermo, Italy, and Menno Huisman, MD, PhD, and Wendy Zondag, MD, Leiden University Medical Center, Leiden, the Netherlands, for sharing unpublished data from their studies; Drahomir Aujesky, MD, Bern University Hospital, Bern, Switzerland, Jeffrey A. Kline, MD, Carolinas Medical Center, Charlotte, North Carolina, and Samuel Z. Goldhaber, MD, Brigham and Women's Hospital, Boston, MA, for serving as our experts on the pulmonary embolism literature; and the ED leadership of the Permanente Medical Group in the Sacramento Valley for their continued enthusiastic support of clinical research.

      Appendix

      Table E1Characteristics of the prospective venous thromboembolic studies excluded from selection.
      First AuthorYearStudy DesignDiagnosis Under StudyCountryCenters, nPatients With PE Treated Without Hospitalization, n
      Atypical outpatient setting
      Olsson
      • Olsson C.G.
      • Bitzen U.
      • Olsson B.
      • et al.
      Outpatient tinzaparin therapy in pulmonary embolism quantified with ventilation/perfusion scintigraphy.
      2006Observational studyPESweden1102
      Outcome measures not described or reported for PE population treated without hospitalization
      Harrison
      • Harrison L.
      • McGinnis J.
      • Crowther M.
      • et al.
      Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin.
      1998Observational study with consecutive samplingDVTCanada22
      Wells
      • Wells P.S.
      • Kovacs M.J.
      • Bormanis J.
      • et al.
      Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin: a comparison of patient self-injection with homecare injection.
      1998Observational study with convenience samplingDVT and PECanada234
      Wilson
      • Wilson SJA G.L.
      • Anderson D.R.
      Outpatient treatment of deep vein thrombosis and pulmonary embolism: a hospital-based program.
      1999Observational study with consecutive samplingDVT and PECanada19
      Savage
      • Savage K.J.
      • Wells P.S.
      • Schulz V.
      • et al.
      Outpatient use of low molecular weight heparin (Dalteparin) for the treatment of deep vein thrombosis of the upper extremity.
      1999Observational study with consecutive samplingDVTCanada21
      Bauld
      • Bauld D.L.
      • Kovacs M.J.
      Dalteparin in emergency patients to prevent admission prior to investigation for venous thromboembolism.
      1999Observational study with convenience samplingSuspected DVT and PECanada19
      Labas
      • Labas P.
      • Ohradka B.
      • Cambal M.
      Could deep vein thrombosis be safely treated at home?.
      2001Observational study with consecutive samplingDVTSlovakia17
      Heaton
      • Heaton D.
      • Han D.Y.
      • Inder A.
      Outpatient treatment of community acquired venous thromboembolism—the Christchurch experience.
      2002Observational studyDVT and PENew Zealand128
      Ageno
      • Ageno W.
      • Steidl L.
      • Marchesi C.
      • et al.
      Selecting patients for home treatment of deep vein thrombosis: the problem of cancer.
      2002Observational studyDVTItaly112
      Arcelus
      • Arcelus J.I.
      • Caprini J.A.
      • Monreal M.
      • et al.
      The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients.
      2003Observational study (prospective registry)DVT and PESpain8118
      Kearon
      • Kearon C.
      • Ginsberg J.S.
      • Julian J.A.
      • et al.
      Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism.
      2006RCT (noninferiority) comparing 2 outpatient pharmacotherapiesDVT and PECanada and New Zealand652
      Santamaria
      • Santamaria A.
      • Juarez S.
      • Reche A.
      • et al.
      Low-molecular-weight heparin, bemiparin, in the outpatient treatment and secondary prophylaxis of venous thromboembolism in standard clinical practice: the ESFERA Study.
      2006Observational study comparing 2 pharmacotherapiesDVT with or without PESpain545
      Hyers
      • Hyers T.M.
      • Spyropoulos A.C.
      Community-based treatment of venous thromboembolism with a low-molecular-weight heparin and warfarin.
      2007Observational studyDVT with or without PEUnited States654
      Zed
      • Zed P.J.
      • Filiatrault L.
      Clinical outcomes and patient satisfaction of a pharmacist-managed, emergency department–based outpatient treatment program for venous thromboembolic disease.
      2008Observational studyDVT and PECanada138
      Hull
      • Hull R.D.
      • Pineo G.F.
      • Brant R.
      • et al.
      Home therapy of venous thrombosis with long-term LMWH versus usual care: patient satisfaction and post-thrombotic syndrome.
      2009RCT comparing 2 outpatient treatment strategiesDVT with or without PECanada2236
      Hacobian
      • Hacobian M.
      • Shetty R.
      • Niles C.M.
      • et al.
      Once daily enoxaparin for outpatient treatment of acute venous thromboembolism: a case-control study.
      2010Case-control study of an investigational outpatient regimenDVT and PEUnited States13 or less
      It is unclear whether the 3 patients with PE in the case group were treated as outpatients or were hospitalized for less than 72 hours.
      DVT, Deep venous thrombosis; PE, pulmonary embolism; RCT, randomized controlled trial.
      low asterisk It is unclear whether the 3 patients with PE in the case group were treated as outpatients or were hospitalized for less than 72 hours.
      Table E2Criteria used to objectively confirm the diagnosis of pulmonary embolism.
      First Author
      Kovacs
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      Beer
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      Wells
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      Siragusa
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      Rodríguez-Cerrillo
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      Agterof
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      Zondag
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      Aujesky
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      Objectively confirmed radiographic examinationYesYes, but details not reportedYesYesYesYesYes, but details not reportedYes
      Spiral CT pulmonary angiographyYes, but details not reportedIntraluminal filling defect in segmental or larger vesselsIntraluminal filling defect in a lobar or main pulmonary arteryYes, but details not reportedIntraluminal filling defectNew contrast filling defect
      Pulmonary AngiographyYes, but details not reportedConstant intraluminal filling defect or an abrupt cutoff of vessels greater than 2.5 mm in diameterIntraluminal filling defectIntraluminal filling defectNew contrast filling defect
      Ventilation perfusion lung scintigraphy
       High probabilityYes, but details not reportedRequires moderate or high pretest clinical probabilityRequires moderate/high clinical probabilityYesYesYes
       Nonhigh (or nondiagnostic) probabilitySymptoms compatible with PE plus confirmed DVT (ultrasonography or venogram)NoRequired high pretest clinical probabilityRequired symptoms compatible with PE plus confirmed DVT by ultrasonographyRequired proximal or distal DVT confirmed by ultrasonographyNo
      Lower extremity compression ultrasonography or contrast venogramYes, with the above lung imagingNoRequired high clinical suspicion of PEYes, with the above lung imagingYes, with the above lung imagingRequired acute-onset dyspnea or chest pain
      PE, Pulmonary embolism; DVT, deep venous thrombosis.
      Table E3Management of outpatients with pulmonary embolism treated without hospitalization.
      First AuthorWeight-Adjusted Low-molecular-weight Heparin (LMWH)
      Administered subcutaneously. Stopped after minimum days of dosing when INR was in the therapeutic range for at least 2 consecutive days.
      Oral Vitamin K Antagonist (VKA)
      In patients with malignancy, LMWH was usually continued in place of a vitamin K antagonist.
      Researcher-Initiated Follow-up During the First WeekEmergency Patient Access
      Kovacs
      • Kovacs M.J.
      • Anderson D.
      • Morrow B.
      • et al.
      Outpatient treatment of pulmonary embolism with dalteparin.
      Dalteparin, first dose usually <2 h of diagnosis; minimum of 5 daysWarfarin begun on day 1. Dosage based on treatment nomogram; INR measurement on days 1, 3, and 5Telephone calls every other day; clinic appointment arranged at 1 wk24-h emergency number provided by which to report study-related symptoms
      Beer
      • Beer J.H.
      • Burger M.
      • Gretener S.
      • et al.
      Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients.
      Nadroparin; minimum of 5 daysPhenprocoumonNot reportedNot reported
      Wells
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.A.
      • et al.
      A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.
      Tinzaparin or dalteparin; minimum of 5 daysWarfarin begun on day 1 or within 24 h of first dose of LMWH; dosage based on treatment nomogramTelephone calls at 24- to 48-h intervals or in-person review; clinic appointment arranged at 1 wkEmergency number provided; patients also were asked to report to study center for study-related symptoms
      Siragusa
      • Siragusa S.
      • Arcara C.
      • Malato A.
      • et al.
      Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.
      LMWH not specifiedAdministered in about half the cases in this population of cancer patients; the other half continued receiving LMWHNot reportedNot reported
      Rodríguez-Cerrillo
      • Rodríguez-Cerrillo M.
      • Alvarez-Arcaya A.
      • Fernandez-Diaz E.
      • et al.
      A prospective study of the management of non-massive pulmonary embolism in the home.
      Enoxaparin or dalteparinAcenocoumarol started on day 4 if not contraindicated; INR measurements on days 1 and 6 and then daily until therapeutic“Hospital-in-home” included daily visits by home health care provider for 7–14 days (mean 8.9)Not reported
      Agterof
      • Agterof M.J.
      • Schutgens R.E.
      • Snijder R.J.
      • et al.
      Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.
      LMWH not specified; first dose usually <3 h of diagnosisTiming, dosage, and anticoagulant not reported; postdischarge monitoring provided by the thrombosis serviceTelephone calls on days 2 and 4. Clinic appointment arranged for day 10.A 24-h emergency number was provided
      Zondag
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study.
      Nadroparin; minimum of 5 daysVKA begun on day 1; postdischarge monitoring provided by the thrombosis serviceClinic appointment arranged at 1 wkPatients were asked to contact their specialist for study-related symptoms
      Aujesky
      • Aujesky D.
      • Roy P.M.
      • Verschuren F.
      • et al.
      Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.
      Enoxaparin; minimum of 5 daysEarly initiation of various agents; no particular regimen was specified; postdischarge monitoring provided by the primary care physician or anticoagulation clinicContacted daily for first wkPatients were asked to report to the emergency department for study-related symptoms
      LMWH, Low-molecular-weight heparin; VKA, vitamin K antagonist; INR, international normalized ratio.
      low asterisk Administered subcutaneously. Stopped after minimum days of dosing when INR was in the therapeutic range for at least 2 consecutive days.
      In patients with malignancy, LMWH was usually continued in place of a vitamin K antagonist.

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      • Correction
        Annals of Emergency MedicineVol. 65Issue 2
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          In the November 2012 issue, regarding the article by Vinson et al (“Can selected patients with newly diagnosed pulmonary embolism be safely treated without hospitalization? A systematic review,” pages 651-662.e4), Table 2 should have stated that the Aujeski trial did not suffer from a lack of allocation concealment.
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