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

PULMONARY/ORIGINAL RESEARCH

Can Selected Patients With Newly Diagnosed Pulmonary Embolism Be Safely Treated Without Hospitalization? A Systematic Review David R. Vinson, MD, Shahriar Zehtabchi, MD, Donald M. Yealy, MD From the Department of Emergency Medicine, Kaiser Permanente Roseville Medical Center, Roseville, CA (Vinson); the Department of Emergency Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY (Zehtabchi); and the Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA (Yealy).

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 lowrisk patients. [Ann Emerg Med. 2012;60:651-662.] Please see page 652 for the Editor’s Capsule Summary of this article. A feedback survey is available with each research article published on the Web at www.annemergmed.com. A podcast for this article is available at www.annemergmed.com. 0196-0644/$-see front matter Copyright © 2012 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2012.05.041

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.1-4 Although a similar site-of-treatment shift for select patients with pulmonary embolism has been recommended by several professional societies,5-8 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.9 Volume , .  : November 

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,10,11 but our approach differs in 3 ways. Annals of Emergency Medicine 651

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Editor’s Capsule Summary

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. 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.12,13 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.14-18 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.10,11 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 652 Annals of Emergency Medicine

Vinson, Zehtabchi & Yealy the patient’s residence for assistance with medication administration.19 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 inpatienttreatment 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.10,11 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 riskstratification 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 Volume , .  : November 

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Titles and Abstracts Screened MEDLINE (n=1,199) and EMBASE (n=559) Aer removal of duplicates: n=1,671 SciVerse Scopus: n=91 CINHAL: n=117 Web of Knowledge: n=47 Cochrane library: n=27 Clinical trial registra
on: n=268 Abstracts from emergency medicine conferences (2008-2011): n=62 Addi
onal studies from hand-based search: n=3 Addi
onal studies from consultants: n=0 Total: 2,286 Ini
al exclusion based on study
tle and abstract: n=2,262 Not directly related to study ques
on or failed to meet eligibility criteria Mee
ng eligibility criteria for full-text review: n=24 Prospec
ve studies including pa
ents with acute, symptoma
c PE discharged home for outpa
ent management without hospitaliza
on

Selected studies: n=8 Observa
onal studies: n=7 Randomized controlled trial comparing 2 sites of treatment: n=1

Exclusion criteria present: n=17 Atypical outpa
ent seng (hotel): n=1 Objec
ve outcome measures not described or reported for the PE popula
on treated en
rely as outpa
ents: n=16

Aempt to collect missing outcome data from larger studies: n=2 Successful: n=1 Unsuccessful: n=1

CINHAL = Cumula
ve Index to Nursing and Allied Health Literature; PE = pulmonary embolism

Figure. Flow diagram of study selection process for systematic review.

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.20,21 In reporting our review, we adhered to the criteria proposed by the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement.22 Primary Data Analysis We calculated interobserver agreement for study selection with Cohen’s ␬. 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. Volume , .  : November 

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)23; and objective outcome measures not described or reported for the pulmonary embolism population treated entirely as outpatients (n⫽16).24-39 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 Annals of Emergency Medicine 653

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studies had 50 or more patients with pulmonary embolism treated exclusively in an outpatient setting.33,39 We contacted these authors and found that the data from Kearon et al33 were not accessible, but the results from Zondag et al39 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. Interobserver agreement for study selection was 100% (␬ 1.0; 95% CI 0.85 to 1.0). Eight studies were selected for systematic review.39-46 Seven of these were observational studies, including 6 prospective cohort studies that describe the outcome of pulmonary embolism patients treated entirely as outpatients39-45 and 1 randomized controlled trial comparing 2 different outpatient treatment regimens.46 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 embolism46 (Table 1). With all 8 studies combined, 777 adult patients (ⱖ18 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.40,42,43 Siragusa et al43 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.40,42 In 4 studies, patients were discharged home directly from the ED.39,44-46 The ED length of stay in the study by Aujesky et al46 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.39,44,45 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.20,47,48 The limitations and quality assessment of the studies are described in Table 2. The significant heterogeneity between the study populations precluded outcome-level assessments. Objective confirmation of the diagnosis of pulmonary embolism was clear in all 8 studies, though 2 failed to describe precisely the radiographic examinations used.39,41 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 embolism43 or ultrasonographically diagnosed deep venous thrombosis.40,44,45 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.43,46 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 al41 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.49 Agterof et al45 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 (ⱖ500 pg/mL). Aujesky et al46 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).50 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.41,45,46 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.39,40,42-44 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). 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.44 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.39,42,45,46 Major bleeding was

654 Annals of Emergency Medicine

Volume , .  : November 

Patients With PE Year

Study Design

Kovacs40

2000

Beer41

2003

Wells42

2005

Siragusa43

2005

RodríguezCerrillo44

2009

Agterof45

2010

Zondag39

2011

Aujesky46

2011

Observational study with consecutive sampling Observational study with convenience sampling RCT comparing 2 outpatient LMWH regimens in DVT and PE pts Observational study with consecutive sampling of patients with cancer Observational study (sampling method unclear) Observational study of patients with NT-proBNP ⬍500 pg/mL Observational study with consecutive sampling RCT comparing inpt/ outpt site of care for PE pts designated low 储 risk by the PESI

Country

Centers, n, Academic/Community

Site of Treatment and Disposition

Total, n*

Discharged Home, n

Mean Age, Years

Sex, % Women NR

Canada

3 academic

Outpatient thrombosis unit

108

81

56.1

Switzerland

2 academic

NR

105

43

69.0

Canada

4 academic

Outpatient thrombosis unit

90

90

57.8

Italy

1 academic

Outpatient thrombosis unit

58

36

61.5

47.3

Spain

1 academic

ED

61

30

66.8

70.0

Netherlands

5 academic

ED

152

105

53.4

Netherlands

12 academic and community

ED

297

229

55.0

Switzerland, France, Belgium, United States

19 academic

ED

317

163

‡

§

†

†

†

¶

†

†

47.0

NR

†

45.9

†

†

51.3

†

42.0

50.9

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. *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. 储 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.

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First Author

Patient Demographics

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Table 1. Characteristics of selected prospective studies of patients with acute, symptomatic pulmonary embolism treated without hospitalization.

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Table 2. Quality assessment of the selected studies of outpatient pulmonary embolism management using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.* Observational Studies

Limitations and Quality Assessment

Kovacs40 Beer41 † Wells42 Siragusa43 Rodríguez-Cerrillo44 Agterof45 Zondag39

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 limitations Overall quality of evidence 1, 3, 4 Very low 1, 3, 4 Very low 1, 3, 4 Very low ‡ 1, 3, 4 Very low 1, 3, 4 Very low 1, 3, 4 Very low 1, 2, 3 Very low

Randomized Controlled Trials

Limitations of Quality Assessment

Aujesky46

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 limitations Overall quality of evidence 1, 2 Moderate

*See references 20 and 21. † 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.

defined according to standard definitions.2,51 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,43 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.39-42,44-46 Even if the 2 venous thromboembolic–related and hemorrhage-related deaths in the one study that reported only 180-day outcomes43 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,39,45,46 a temporal horizon of interest to emergency physicians.52 656 Annals of Emergency Medicine

Two studies measured patient satisfaction. Agterof et al45 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,46 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 metaanalysis of outcomes. Volume , .  : November 

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Table 3. Outpatient ineligibility criteria for patients with acute symptomatic pulmonary embolism. First Author Kovacs40 Beer41 Wells42 Siragusa43 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 Symptoms Severe pain (often chest) requiring parenteral opioids Vital signs Hemodynamic instability or hypotension Tachycardia Hypoxemia or oxygen requirement 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 Heart failure 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

RodríguezCerrillo44

✓

Agterof45 Zondag39 Aujesky46 ✓

✓

✓

✓

✓

✓ ✓

✓ ✓

✓ ✓

✓ ✓

✓

✓

✓

✓ ✓ § ✓ ✓

✓ ‡ ✓ ✓

‡

✓

✓

‡

✓

✓

✓ ✓ ✓

✓

✓

✓

✓

✓ ✓

✓ ✓ ✓ ✓

✓

✓

✓

✓

✓

✓

✓ ✓

✓

✓

✓

✓ ✓ ✓

✓ ✓ ✓

✓

✓

✓ ✓

†

✓*

✓ ‡ ✓

✓

✓

✓ ✓ ✓

✓ ✓

储

✓ ✓

✓

✓

✓

✓

✓

✓ ✓ ✓

✓ ✓ ✓

‡

✓ ✓

✓ ✓ ✓ ✓ ✓

✓ ✓ ✓

✓ ✓

✓

✓ ✓ ✓ ✓ ✓

*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%. 储 Patients were excluded if they had a medical or social reason to be in the hospital for more than 24 hours.

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Annals of Emergency Medicine 657

Mortality

First Author Observational studies Kovacs40 Beer41 Wells42 Siragusa43 Rodríguez-Cerrillo44 Agterof45

Nonfatal Events

Patients n

Endpoint, Days

Overall Mortality, n (%, 95% CI)*

VTE-Related Mortality, n (%, 95% CI)

Hemorrhage-Related Mortality, n (%, 95% CI)

VTE Recurrence, n (%, 95% CI)

Major Bleeding Event, n (%, 95% CI)

81 43 90 36 30 105

90 90 90 180 90 10 90 90

4 (4.9, 1.6–12.4) 0 (9.8) 3 (3.3, 0.7–9.8) 11 (30.6, 17.9–47.0) 0 (11.6) 0 (4.2) 0 (4.2) 2 (0.9, 0–3.3)

0 (5.4) 0 (9.8) 0 (4.9) † 2 (5.6, 0.6–19.1) 0 (11.6) 0 (4.2) 0 (4.2) 0 (2.0)

0 (5.4) 0 (9.8) 0 (4.9) † 0 (11.5) 0 (11.6) 0 (4.2) 0 (4.2) 0 (2.0)

5 (6.2, 2.3–14.0) 1 (2.3, 0–13.2) 2 (2.2, 0.1–8.2) 2 (5.6, 0.6–19.1) 0 (11.6) 0 (4.2) 0 (4.2) § 4 (1.7, 0.5–4.6)

1 (1.2, 0.01–7.3) 0 (9.8) 0 (0, 0–4.9) 1 (2.8, 0.01–15.4) 0 (11.6) 0 (4.2) 0 (4.2) 0 (2.0)

0 (2.6) 0 (2.8) 0 (2.7) 0 (2.9)

0 (2.6) 0 (2.8) 0 (2.7) 0 (2.9)

0 (2.6) 1 (0.6, 0.1–3.7) 0 (2.7) 0 (2.9)

2 (1.2, 0.1– 4.4) 2 (1.2, 0.1– 4.6) 0 (2.7) 0 (2.9)

‡

Zondag39 229 Randomized controlled trial 储 Aujesky46 Outpatients 171 163 Inpatients 168 154

14 90 14 90

0 (2.6) 1 (0.6, 0.1–3.7) 0 (2.7) 1 (0.7, 0 – 4.0)

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Table 4. Outcomes of outpatients with pulmonary embolism treated without hospitalization.

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VTE, Venous thromboembolism. *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. 储 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.

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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.53

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 perprotocol cohorts for 90-day mortality was very low (2.1%) (Table 4).46 The study by Aujesky et al46 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 al13 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 shortterm mortality rate. In contrast to other studies, notably that by Aujesky et al,46 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 al13 as discharge after 3 or 5 days of hospitalization. The duration from presentation to ED discharge in the study by Aujesky et al46 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).57,58 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.59 Only 3 of our 8 studies used an explicit risk-stratification tool,41,45,46 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.60,61 Prognostic models are developed to provide objective estimates of outcome probabilities to complement clinical intuition and judgment.62,63 The most rigorously studied validated riskstratification 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

DISCUSSION Changing common practice is difficult for a condition like acute pulmonary embolism, in which serious complications occur in a limited few.54 Physicians often overestimate the risk of harm with novel treatment strategies or assume hospitalbased 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 patients43 (Table 4). The presence of cancer is known to increase the incidence of adverse events in patients being treated for pulmonary embolism,55 though outpatient pulmonary embolism management has still been undertaken successfully in this population.31,56 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).39,40,42,44,45 One study did not report the prevalence of cancer in their population.41 Cancer prevalence may also have had a bearing on the low adverse event rates of the randomized trial.46 Aujesky et al46 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, lowrisk 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 al46 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 Volume , .  : November 

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Outpatient Management of Patients With Pulmonary Embolism treated entirely as outpatients.17,18,64 In contrast, a recent large pulmonary embolism registry from 22 EDs in the United States54 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 siteof-treatment decisions.40,42-44,46 No study assessed in a structured fashion a priori patient knowledge or site-oftreatment preferences, an important part of implementing any care plan.65 Both studies that measured satisfaction after care found high ratings for those treated exclusively as outpatients.45,46 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.66,67 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.68 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.

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Vinson, Zehtabchi & Yealy Supervising editor: Steven M. Green, MD Author contributions: DRV conceived the study and all authors contributed to its design. DRV and SZ retrieved and summarized the data. DRV drafted the article, and all authors contributed substantively to its critical revision and its final approval. DRV takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www. icmje.org). Dr. Yealy received federal funding for prior research on pulmonary embolism: 1R01HL085565-01 and 1K12 HL109068-01. Publication dates: Received for publication April 30, 2012. Revision received May 25, 2012. Accepted for publication May 31, 2012. Available online September 1, 2012. Address for correspondence: David R. Vinson, MD, E-mail [email protected].

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11. Squizzato A, Galli M, Dentali F, et al. Outpatient treatment and early discharge of symptomatic pulmonary embolism: a systematic review. Eur Respir J. 2009;33:1148-1155. 12. Davies CW, Wimperis J, Green ES, et al. Early discharge of patients with pulmonary embolism: a two-phase observational study. Eur Respir J. 2007;30:708-714. 13. Otero R, Uresandi F, Jimenez D, et al. Home treatment in pulmonary embolism. Thromb Res. 2010;126:e1-5. 14. Ong BS, Karr MA, Chan DK, et al. Management of pulmonary embolism in the home. Med J Aust. 2005;183:239-242. 15. Dager WE, King JH, Branch JM, et al. Tinzaparin in outpatients with pulmonary embolism or deep vein thrombosis. Ann Pharmacother. 2005;39:1182-1187. 16. Lui B, Tran A, Montalto M. Treatment of patients with pulmonary embolism entirely in Hospital in the Home. Aust Fam Physician. 2007;36:381-384. 17. Erkens PM, Gandara E, Wells P, et al. Safety of outpatient treatment in acute pulmonary embolism. J Thromb Haemost. 2010;8:2412-2417. 18. Kovacs MJ, Hawel JD, Rekman JF, et al. Ambulatory management of pulmonary embolism: a pragmatic evaluation. J Thromb Haemost. 2010;8:2406-2411. 19. Shepperd S, Doll H, Angus RM, et al. Avoiding hospital admission through provision of hospital care at home: a systematic review and meta-analysis of individual patient data. CMAJ. 2009;180: 175-182. 20. Guyatt GH, Oxman AD, Schunemann HJ, et al. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64:380-382. 21. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924-926. 22. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. 23. Olsson CG, Bitzen U, Olsson B, et al. Outpatient tinzaparin therapy in pulmonary embolism quantified with ventilation/ perfusion scintigraphy. Med Sci Monit. 2006;12:PI9-13. 24. Harrison L, McGinnis J, Crowther M, et al. Assessment of outpatient treatment of deep-vein thrombosis with low-molecularweight heparin. Arch Intern Med. 1998;158:2001-2003. 25. Wells PS, Kovacs MJ, 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. Arch Intern Med. 1998;158:1809-1812. 26. Wilson SJA GL, Anderson DR. Outpatient treatment of deep vein thrombosis and pulmonary embolism: a hospital-based program. Can J Hosp Pharm. 1999;52:282-288. 27. Savage KJ, Wells PS, Schulz V, et al. Outpatient use of low molecular weight heparin (Dalteparin) for the treatment of deep vein thrombosis of the upper extremity. Thromb Haemost. 1999; 82:1008-1010. 28. Bauld DL, Kovacs MJ. Dalteparin in emergency patients to prevent admission prior to investigation for venous thromboembolism. Am J Emerg Med. 1999;17:11-15. 29. Labas P, Ohradka B, Cambal M. Could deep vein thrombosis be safely treated at home? Bratisl Lek Listy. 2001;102:458-461. 30. Heaton D, Han DY, Inder A. Outpatient treatment of community acquired venous thromboembolism—the Christchurch experience. N Z Med J. 2002;115:U105. 31. Ageno W, Steidl L, Marchesi C, et al. Selecting patients for home treatment of deep vein thrombosis: the problem of cancer. Haematologica. 2002;87:286-291.

32. Arcelus JI, Caprini JA, Monreal M, et al. The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients. J Vasc Surg. 2003;38:916-922. 33. Kearon C, Ginsberg JS, Julian JA, et al. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006;296:935-942. 34. 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. Int J Clin Pract. 2006;60:518-525. 35. Hyers TM, Spyropoulos AC. Community-based treatment of venous thromboembolism with a low-molecular-weight heparin and warfarin. J Thromb Thrombolysis. 2007;24:225-232. 36. Zed PJ, Filiatrault L. Clinical outcomes and patient satisfaction of a pharmacist-managed, emergency department– based outpatient treatment program for venous thromboembolic disease. CJEM. 2008;10:10-17. 37. Hull RD, Pineo GF, Brant R, et al. Home therapy of venous thrombosis with long-term LMWH versus usual care: patient satisfaction and post-thrombotic syndrome. Am J Med. 2009; 122:762-769.e3. 38. Hacobian M, Shetty R, Niles CM, et al. Once daily enoxaparin for outpatient treatment of acute venous thromboembolism: a casecontrol study. Clin Appl Thromb Hemost. 2010;16:21-25. 39. Zondag W, Mos IC, Creemers-Schild D, et al. Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost. 2011;9:1500-1507. 40. Kovacs MJ, Anderson D, Morrow B, et al. Outpatient treatment of pulmonary embolism with dalteparin. Thromb Haemost. 2000;83: 209-211. 41. Beer JH, Burger M, Gretener S, et al. Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients. J Thromb Haemost. 2003;1:186-187. 42. Wells PS, Anderson DR, Rodger MA, et al. A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism. Arch Intern Med. 2005;165:733-738. 43. Siragusa S, Arcara C, Malato A, et al. Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients. Ann Oncol. 2005;16(suppl 4):iv136-139. 44. 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. Eur J Intern Med. 2009;20:598-600. 45. Agterof MJ, Schutgens RE, Snijder RJ, et al. Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level. J Thromb Haemost. 2010;8:1235-1241. 46. Aujesky D, Roy PM, Verschuren F, et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet. 2011;378:41-48. 47. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383-394. 48. Guyatt GH, Norris SL, 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. Chest. 2012;141: 53S-70S. 49. Wicki J, Perrier A, Perneger TV, et al. Predicting adverse outcome in patients with acute pulmonary embolism: a risk score. Thromb Haemost. 2000;84:548-552.

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Outpatient Management of Patients With Pulmonary Embolism 50. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med. 2005;172:1041-1046. 51. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in nonsurgical patients. J Thromb Haemost. 2005;3:692-694. 52. Kabrhel C, Sacco W, Liu S, et al. Outcomes considered most important by emergency physicians when determining disposition of patients with pulmonary embolism. Int J Emerg Med. 2010;3:239-264. 53. Guyatt GH, Oxman AD, Montori V, et al. GRADE guidelines: 5. Rating the quality of evidence—publication bias. J Clin Epidemiol. 2011;64:1277-1282. 54. Pollack CV, Schreiber D, Goldhaber SZ, 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). J Am Coll Cardiol. 2011;57:700-706. 55. Connolly GC, Khorana AA. Risk stratification for cancer-associated venous thromboembolism. Best Pract Res Clin Haematol. 2009; 22:35-47. 56. Ageno W, Grimwood R, Limbiati S, et al. Home-treatment of deep vein thrombosis in patients with cancer. Haematologica. 2005; 90:220-224. 57. Baugh CW, Venkatesh AK, Bohan JS. Emergency department observation units: a clinical and financial benefit for hospitals. Health Care Manage Rev. 2011;36:28-37. 58. Wiler JL, Ross MA, Ginde AA. National study of emergency department observation services. Acad Emerg Med. 2011;18: 959-965.

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Vinson, Zehtabchi & Yealy 59. Bledsoe J, Hamilton D, Bess E, et al. Treatment of low-risk pulmonary embolism patients in a chest pain unit. Crit Pathw Cardiol. 2010;9:212-215. 60. Jimenez D, Aujesky D, Yusen RD. Risk stratification of normotensive patients with acute symptomatic pulmonary embolism. Br J Haematol. 2010;151:415-424. 61. Geersing GJ, Oudega R, Hoes AW, et al. Managing pulmonary embolism using prognostic models: future concepts for primary care. CMAJ. 2012;184:305-310. 62. Moons KG, Altman DG, Vergouwe Y, et al. Prognosis and prognostic research: application and impact of prognostic models in clinical practice. BMJ. 2009;338:b606. 63. Moons KG, Kengne AP, Grobbee DE, et al. Risk prediction models: II. External validation, model updating, and impact assessment. Heart. 2012;98:691-698. 64. Baglin T. Fifty per cent of patients with pulmonary embolism can be treated as outpatients. J Thromb Haemost. 2010;8:24042405. 65. Hess EP, Knoedler MA, Shah ND, et al. The chest pain choice decision aid: a randomized trial. Circ Cardiovasc Qual Outcomes. 2012;5:251-259. 66. Ansell J, Askin D. New targets for anticoagulation and future perspectives. Curr Drug Discov Technol. 2012;9:150-155. 67. Ansell J. Will the new target-specific oral anticoagulants improve the treatment of venous thromboembolism? Thromb Haemost. 2012;107:1009-1011. 68. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.

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Figure E1. MEDLINE search strategy.

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Table E1. Characteristics of the prospective venous thromboembolic studies excluded from selection.

First Author

Year

Study Design

Diagnosis Under Study

Country

Atypical outpatient setting Olsson23 2006 Observational study PE Sweden Outcome measures not described or reported for PE population treated without hospitalization Harrison24 1998 Observational study DVT Canada with consecutive sampling Wells25 1998 Observational study DVT and PE Canada with convenience sampling Wilson26 1999 Observational study DVT and PE Canada with consecutive sampling Savage27 1999 Observational study DVT Canada with consecutive sampling Bauld28 1999 Observational study Suspected DVT Canada with convenience and PE sampling Labas29 2001 Observational study DVT Slovakia with consecutive sampling Heaton30 2002 Observational study DVT and PE New Zealand 2002 Observational study DVT Italy Ageno31 Arcelus32 2003 Observational study DVT and PE Spain (prospective registry) Kearon33 2006 RCT (noninferiority) DVT and PE Canada and comparing 2 New outpatient Zealand pharmacotherapies Santamaria34 2006 Observational study DVT with or Spain comparing 2 without PE pharmacotherapies Hyers35 2007 Observational study DVT with or United without PE States 2008 Observational study DVT and PE Canada Zed36 Hull37 2009 RCT comparing 2 DVT with or Canada outpatient without PE treatment strategies Hacobian38 2010 Case-control study DVT and PE United of an States investigational outpatient regimen

Centers, n

Patients With PE Treated Without Hospitalization, n

1

102

2

2

2

34

1

9

2

1

1

9

1

7

1 1 81

28 12 18

6

52

54

5

65

4

1 22

38 36

1

3 or less*

DVT, Deep venous thrombosis; PE, pulmonary embolism; RCT, randomized controlled trial. *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.

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Table E2. Criteria used to objectively confirm the diagnosis of pulmonary embolism. First Author 40

41

Kovacs

42

Beer

Wells

Yes

Pulmonary Angiography

Yes, but details not reported

—

Constant intraluminal filling defect or an abrupt cutoff of vessels greater than 2.5 mm in diameter

Yes, but details not reported

—

Symptoms compatible with PE plus confirmed DVT (ultrasonography or venogram) Yes, with the above lung imaging

—

Requires moderate or high pretest clinical probability No

—

No

Ventilation perfusion lung scintigraphy High probability

Nonhigh (or nondiagnostic) probability

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Lower extremity compression ultrasonography or contrast venogram

PE, Pulmonary embolism; DVT, deep venous thrombosis.

Siragusa

Rodríguez-Cerrillo44

Agterof45

Zondag39

Aujesky46

Yes

Yes

Yes

Yes

Yes, but details Yes not reported — New contrast filling defect

Intraluminal filling defect in segmental or larger vessels

Intraluminal filling defect in a lobar or main pulmonary artery Intraluminal filling defect

Yes, but details not reported

Intraluminal filling defect

—

Intraluminal filling defect

—

New contrast filling defect

Requires moderate/high clinical probability

Yes

Yes

—

Yes

Required high pretest clinical probability

Required symptoms compatible with PE plus confirmed DVT by ultrasonography

Required proximal or distal DVT confirmed by ultrasonography

—

No

Required high clinical suspicion of PE

Yes, with the above lung imaging

Yes, with the above lung imaging

—

Required acuteonset dyspnea or chest pain

Outpatient Management of Patients With Pulmonary Embolism

Objectively confirmed radiographic examination Spiral CT pulmonary angiography

Yes, but details not reported

Yes, but details not reported —

43

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Table E3. Management of outpatients with pulmonary embolism treated without hospitalization. Weight-Adjusted Low-molecularweight Heparin (LMWH)*

Oral Vitamin K Antagonist † (VKA)

Kovacs40

Dalteparin, first dose usually ⬍2 h of diagnosis; minimum of 5 days

Beer41 Wells42

Nadroparin; minimum of 5 days Tinzaparin or dalteparin; minimum of 5 days

Warfarin begun on day 1. Dosage based on treatment nomogram; INR measurement on days 1, 3, and 5 Phenprocoumon Warfarin begun on day 1 or within 24 h of first dose of LMWH; dosage based on treatment nomogram

Siragusa43

LMWH not specified

Rodríguez-Cerrillo44

Enoxaparin or dalteparin

Agterof45

LMWH not specified; first dose usually ⬍3 h of diagnosis

Zondag39

Nadroparin; minimum of 5 days

Aujesky46

Enoxaparin; minimum of 5 days

First Author

Researcher-Initiated Follow-up During the First Week Telephone calls every other day; clinic appointment arranged at 1 wk Not reported Telephone calls at 24- to 48-h intervals or inperson review; clinic appointment arranged at 1 wk

Administered in about half the cases in this population of cancer patients; the other half continued receiving LMWH Acenocoumarol started on day 4 if not contraindicated; INR measurements on days 1 and 6 and then daily until therapeutic Timing, dosage, and anticoagulant not reported; postdischarge monitoring provided by the thrombosis service VKA begun on day 1; postdischarge monitoring provided by the thrombosis service

Not reported

Early initiation of various agents; no particular regimen was specified; postdischarge monitoring provided by the primary care physician or anticoagulation clinic

Contacted daily for first wk

Emergency Patient Access 24-h emergency number provided by which to report study-related symptoms Not reported Emergency number provided; patients also were asked to report to study center for studyrelated symptoms Not reported

“Hospital-in-home” included daily visits by home health care provider for 7–14 days (mean 8.9)

Not reported

Telephone calls on days 2 and 4. Clinic appointment arranged for day 10.

A 24-h emergency number was provided

Clinic appointment arranged at 1 wk

Patients were asked to contact their specialist for study-related symptoms Patients 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. *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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