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Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Suspected Acute Venous Thromboembolic Disease

      Members of the American College of Emergency Physicians Clinical Policies Committee (Oversight Committee):Michael D. Brown, MD, MSc (Chair 2014-2017; Co-Chair 2017-2018)Stephen J. Wolf, MD (Co-Chair 2017-2018)Richard Byyny, MD, MSc (Methodologist)Deborah B. Diercks, MD, MScSeth R. Gemme, MDCharles J. Gerardo, MD, MHSSteven A. Godwin, MDSigrid A. Hahn, MD, MPHNicholas E. Harrison, MD (EMRA Representative 2017-2018)Benjamin W. Hatten, MD, MPHJason S. Haukoos, MD, MSc (Methodologist)Amy Kaji, MD, MPH, PhD (Methodologist)Heemun Kwok, MD, MS (Methodologist)Bruce M. Lo, MD, MBA, RDMSSharon E. Mace, MDDevorah J. Nazarian, MDJean A. Proehl, RN, MN, CEN, CPEN, TCRN (ENA Representative 2015-2018)Susan B. Promes, MD, MBAKaushal H. Shah, MDRichard D. Shih, MDScott M. Silvers, MDMichael D. Smith, MD, MBAMolly E. W. Thiessen, MDChristian A. Tomaszewski, MD, MS, MBAJonathan H. Valente, MDStephen P. Wall, MD, MSc, MAEd (Methodologist)Stephen V. Cantrill, MD (Liaison with Quality and Patient Safety Committee, and E-QUAL Steering Committee)Jon Mark Hirshon, MD, PhD, MPH (Board Liaison 2016-2018)Travis Schulz, MLS, AHIP, Staff Liaison, Clinical Policies CommitteeRhonda R. Whitson, RHIA, Staff Liaison, Clinical Policies Committee and Subcommittee Revising the Venous Thromboembolic Disease Policy
      Policy statements and clinical policies are the official policies of the American College of Emergency Physicians and, as such, are not subject to the same peer review process as articles appearing in the journal. Policy statements and clinical policies of ACEP do not necessarily reflect the policies and beliefs of Annals of Emergency Medicine and its editors.

      Abstract

      This clinical policy from the American College of Emergency Physicians addresses key issues in the evaluation and management of adult patients with suspected venous thromboembolism. A writing subcommittee conducted a systematic review of the literature to derive evidence-based recommendations to answer the following clinical questions: (1) In adult patients with suspected acute pulmonary embolism, can a clinical prediction rule be used to identify a group of patients at very low risk for the diagnosis of pulmonary embolism for whom no additional diagnostic workup is required? (2) In adult patients with low to intermediate pretest probability for acute pulmonary embolism, does a negative age-adjusted D-dimer result identify a group of patients at very low risk for the diagnosis of pulmonary embolism for whom no additional diagnostic workup is required? (3) In adult patients with subsegmental pulmonary embolism, is it safe to withhold anticoagulation? (4) In adult patients diagnosed with acute pulmonary embolism, is initiation of anticoagulation and discharge from the emergency department safe? (5) In adult patients diagnosed with acute lower-extremity deep venous thrombosis who are discharged from the ED, is treatment with a non–vitamin K antagonist oral anticoagulant safe and effective compared with treatment with low-molecular-weight heparin and vitamin K antagonist? Evidence was graded and recommendations were made based on the strength of the available data.

      Introduction

      Venous thromboembolism (VTE), a coagulation disorder encompassing both deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major public health problem.
      Office of the Surgeon General (US); National Heart, Lung, and Blood Institute (US)
      The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism.
      • Beckman M.G.
      • Hooper W.C.
      • Critchley S.E.
      • et al.
      Venous thromboembolism: a public health concern.
      Undiagnosed, untreated patients are believed to be at substantial risk for progressive disease and sudden death, typically because of worsening right-sided heart strain and, ultimately, cardiovascular collapse. Treated patients are at risk for chronic sequelae (eg, vein scarring, leg swelling, pulmonary hypertension) and adverse events from ongoing anticoagulation (eg, hemorrhage, medication adverse effects).
      Although the true incidence of VTE is not known, reports estimate that 600,000 to 900,000 individuals per year (1 to 2 per 1,000) may be affected in the United States, a number that increases with patient age.
      • Beckman M.G.
      • Hooper W.C.
      • Critchley S.E.
      • et al.
      Venous thromboembolism: a public health concern.
      • Heit J.A.
      The epidemiology of venous thromboembolism in the community.
      • Oger E.
      Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group.
      Others estimate that upwards of 294,000 fatal cases of PE occur in the United States annually, accounting for up to 10% of all hospital deaths.
      • Heit J.A.
      • Cohen A.T.
      • Anderson Jr., F.A.
      Estimated annual number of incident and recurrent, non-fatal and fatal venous thromboembolism (VTE) events in the U.S.
      • Cohen A.T.
      • Agnelli G.
      • Anderson F.A.
      • et al.
      Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality.
      In selected patient populations, VTE has been reported to have an associated mortality rate as low as 2%
      • Jiménez D.
      • de Miguel-Díez J.
      • Guijarro R.
      • et al.
      for the RIETE Investigators
      Trends in the management and outcomes of acute pulmonary embolism. Analysis from the RIETE registry.
      and as high as 30%, which is primarily attributed to PE.
      • Beckman M.G.
      • Hooper W.C.
      • Critchley S.E.
      • et al.
      Venous thromboembolism: a public health concern.
      • Heit J.A.
      The epidemiology of venous thromboembolism in the community.
      • Cushman M.
      • Tsai A.W.
      • White R.H.
      • et al.
      Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology.
      One significant challenge to health care providers evaluating patients for VTE lies in the variability of signs and symptoms of the disease that are related to the clot burden, location, and the individual patient’s cardiopulmonary reserve. Without perfect, cost-effective tests for the diagnosis, providers have come to rely on Bayesian decisionmaking to guide their workup, using pretest probability to interpret diagnostic evaluations and generate posttest probability of disease.
      • Fesmire F.M.
      • Brown M.D.
      • Espinosa J.A.
      • et al.
      American College of Emergency Physicians
      Critical issues in the evaluation and management of adult patients presenting to the emergency department with pulmonary embolism.
      • Raja A.S.
      • Greenberg J.O.
      • Qaseem A.
      • et al.
      Clinical Guidelines Committee of the American College of Physicians
      Evaluation of patients with suspected acute pulmonary embolism: best practice advice from the Clinical Guidelines Committee of the American College of Physicians.
      Doing this allows providers to maximize diagnostic accuracy while minimizing overtesting and patient harm from the risks associated with unnecessary evaluation and treatment.
      Efforts to refine this Bayesian approach in emergency medicine have been ongoing. Original studies to determine pretest probability and the accuracy of various screening tests
      • Wells P.S.
      • Ginsberg J.S.
      • Anderson D.R.
      • et al.
      Use of a clinical model for safe management of patients with suspected pulmonary embolism.
      • Le Gal G.
      • Righini M.
      • Roy P.-M.
      • et al.
      Prediction of pulmonary embolism in the emergency department: the revised Geneva score.
      • Aujesky D.
      • Obrosky D.S.
      • Stone R.A.
      • et al.
      Derivation and validation of a prognostic model for pulmonary embolism.
      have been validated, and the limits of their efficacy are being explored.
      • Fabiá Valls M.J.
      • van der Hulle T.
      • den Exter P.L.
      • et al.
      Performance of a diagnostic algorithm based on a prediction rule, D-dimer and CT-scan for pulmonary embolism in patients with previous venous thromboembolism. A systematic review and meta-analysis.
      These structured clinical prediction rules, whether diagnostic (eg, Pulmonary Embolism Rule-out Criteria [PERC], Wells criteria, revised Geneva score [RGS]), or prognostic (eg, Pulmonary Embolism Severity Index [PESI], Hestia criteria), offer an adjunct to gestalt clinical assessment to assist in risk stratification and determination of pretest probability (ie, low, intermediate, high, nonhigh, PE unlikely, PE likely) or predict prognosis. In consideration of the cost of evaluation, the risk of false positives, and the risk of complications related to testing, studies have supported using a predefined posttest probability threshold of less than 2.0% to exclude the diagnosis of VTE.
      • Fesmire F.M.
      • Brown M.D.
      • Espinosa J.A.
      • et al.
      American College of Emergency Physicians
      Critical issues in the evaluation and management of adult patients presenting to the emergency department with pulmonary embolism.
      • Fabiá Valls M.J.
      • van der Hulle T.
      • den Exter P.L.
      • et al.
      Performance of a diagnostic algorithm based on a prediction rule, D-dimer and CT-scan for pulmonary embolism in patients with previous venous thromboembolism. A systematic review and meta-analysis.
      • Pauker S.G.
      • Kassirer J.P.
      The threshold approach to clinical decision making.
      • Lessler A.L.
      • Isserman J.A.
      • Agarwal R.
      • et al.
      Testing low-risk patients for suspected pulmonary embolism: a decision analysis.
      • Pines J.M.
      • Lessler A.L.
      • Ward M.J.
      • et al.
      The mortality benefit threshold for patients with suspected pulmonary embolism.
      • Sikkens J.J.
      • Beekman D.G.
      • Thijs A.
      • et al.
      How much overtesting is needed to safely exclude a diagnosis? a different perspective on triage testing using Bayes' theorem.
      Last, substantial efforts are being made to advance the treatment of VTE by balancing outcomes, anticoagulation risks to patients, and patient preferences. New non–vitamin K antagonist oral anticoagulants (NOACs) (aka novel oral anticoagulants, direct oral anticoagulants, and target-specific oral anticoagulants) directly bind to specific clotting factors (ie, IIa or Xa) to induce anticoagulation, and have been proposed as safer alternatives to vitamin K antagonists (VKAs) (ie, warfarin), which more broadly reduce circulating clotting factors (ie, II, VI, IX, and X). NOACs are particularly appealing for long-term anticoagulation because of their simple oral dosing regimens with no need for routine laboratory monitoring. Examples of approved NOACs include apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Savaysa), and rivaroxaban (Xarelto).
      The 2011 American College of Emergency Physicians (ACEP) clinical policy on this topic focused on 6 critical questions: pretest probability and clinical assessment, utility of the PERC, the diagnostic role of highly sensitive D-dimer assays, computed tomography (CT) pulmonary angiogram, CT venogram, and the therapeutic role of thrombolysis in hemodynamically stable and unstable patients with PE.
      • Fesmire F.M.
      • Brown M.D.
      • Espinosa J.A.
      • et al.
      American College of Emergency Physicians
      Critical issues in the evaluation and management of adult patients presenting to the emergency department with pulmonary embolism.
      This revision will focus on 5 areas of interest or controversy that have developed or still exist since the 2011 policy was formulated. The first 2 critical questions address the role of unique clinical prediction rules and age-adjusted D-dimer testing in the diagnosis of PE, whereas the remaining 3 questions focus on optimal treatment and disposition for individuals receiving a diagnosis of venous thromboembolic disease.

      Methodology

      This clinical policy is based on a systematic review with critical analysis of the medical literature meeting the inclusion criteria. Searches of MEDLINE, MEDLINE InProcess, SCOPUS, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews, were performed. All searches were limited to English-language sources, adults, and human studies. Specific key words/phrases, years used in the searches, dates of searches, and study selection are identified under each critical question. In addition, relevant articles from the bibliographies of included studies and more recent articles identified by committee members and reviewers were included.
      This policy is a product of the ACEP clinical policy development process, including internal and external review, and is based on the existing literature; when literature was not available, consensus of Clinical Policies Committee members was used and noted as such in the recommendation (ie, consensus recommendation). Review comments were received from emergency physicians and residents, internal and cardiovascular medicine physicians, a pharmaceutical industry representative, an advocate for patient safety, ACEP’s Medical-Legal Committee, the American College of Chest Physicians, and a member of the American College of Physicians. Comments were received during a 60-day open-comment period, with notices of the comment period sent in an e-mail to ACEP members, published in EM Today, posted on the ACEP Web site, and sent to other pertinent physician organizations. The responses were used to further refine and enhance this clinical policy; however, responses do not imply endorsement. Clinical policies are scheduled for revision every 3 years; however, interim reviews are conducted when technology, methodology, or the practice environment changes significantly. ACEP was the funding source for this clinical policy.

       Assessment of Classes of Evidence

      Two methodologists independently graded and assigned a preliminary Class of Evidence for all articles used in the formulation of this clinical policy. Class of Evidence is delineated whereby an article with design 1 represents the strongest study design and subsequent design classes (ie, design 2 and design 3) represent respectively weaker study designs for therapeutic, diagnostic, or prognostic studies, or meta-analyses (Appendix A). Articles are then graded on dimensions related to the study’s methodological features, such as randomization processes, blinding, allocation concealment, methods of data collection, outcome measures and their assessment, selection and misclassification biases, sample size, generalizability, data management, analyses, congruence of results and conclusions, and conflicts of interest. Using a predetermined process combining the study’s design, methodological quality, and applicability to the critical question, articles received a Class of Evidence grade. An adjudication process involving discussion with the original methodologist graders and at least one additional methodologist was then used to address any discordance in original grading, resulting in a final Class of Evidence assignment (ie, Class I, Class II, Class III, or Class X) (Appendix B). Articles identified with fatal flaws or ultimately determined to not be applicable to the critical question received a Class of Evidence grade “X” and were not used in formulating recommendations for this policy. However, content in these articles may have been used to formulate the background and to inform expert consensus in the absence of robust evidence. Grading was done with respect to the specific critical questions; thus, the Class of Evidence for any one study may vary according to the question for which it is being considered. As such, it was possible for a single article to receive a different Class of Evidence rating when addressing a different critical question. Question-specific Classes of Evidence grading may be found in the Evidentiary Table included at the end of this policy.

       Translation of Classes of Evidence to Recommendation Levels

      Based on the strength of evidence grading for each critical question (ie, Evidentiary Table), the subcommittee drafted the recommendations and the supporting text synthesizing the evidence using the following guidelines:

       Level A recommendations

      Generally accepted principles for patient care that reflect a high degree of clinical certainty (eg, based on evidence from 1 or more Class of Evidence I or multiple Class of Evidence II studies).

       Level B recommendations

      Recommendations for patient care that may identify a particular strategy or range of strategies that reflect moderate clinical certainty (eg, based on evidence from 1 or more Class of Evidence II studies or strong consensus of Class of Evidence III studies).

       Level C recommendations

      Recommendations for patient care that are based on evidence from Class of Evidence III studies or, in the absence of any adequate published literature, based on expert consensus. In instances where consensus recommendations are made, “consensus” is placed in parentheses at the end of the recommendation.
      The recommendations and evidence synthesis were then reviewed and revised by the Clinical Policies Committee, which was informed by additional evidence or context gained from reviewers.
      There are certain circumstances in which the recommendations stemming from a body of evidence should not be rated as highly as the individual studies on which they are based. Factors such as consistency of results, uncertainty about effect magnitude, and publication bias, among others, might lead to a downgrading of recommendations.
      When possible, clinically oriented statistics (eg, likelihood ratios, number needed to treat) are presented to help the reader better understand how the results may be applied to the individual patient (Appendix C).
      This policy is not intended to be a complete manual on the evaluation and management of patients with suspected or known acute VTE but rather a focused examination of critical issues that have particular relevance to the current practice of emergency medicine. Potential benefits and harms of implementing recommendations are briefly summarized within each critical question.
      It is the goal of the Clinical Policies Committee to provide an evidence-based recommendation when the medical literature provides enough quality information to answer a critical question. When the medical literature does not contain adequate empirical data to answer a critical question, the members of the Clinical Policies Committee believe that it is equally important to alert emergency physicians to this fact.
      This clinical policy is not intended to represent a legal standard of care for emergency physicians. Recommendations offered in this policy are not intended to represent the only diagnostic or management options available to the emergency physician. ACEP recognizes the importance of the individual physician’s judgment and patient preferences. This guideline provides clinical strategies for which medical literature exists to answer the critical questions addressed in this policy.

       Scope of Application

      This guideline is intended for physicians working in emergency departments (EDs).

       Inclusion Criteria

      This guideline is intended for adult patients presenting to the ED with suspected or known acute VTE (ie, PE or DVT).

       Exclusion Criteria

      This guideline is not intended to address the care of pediatric patients, or those with VTE in the setting of cardiac arrest or pregnancy.

      Critical Questions

      • 1.
        In adult patients with suspected acute PE, can a clinical prediction rule be used to identify a group of patients at very low risk for the diagnosis of PE for whom no additional diagnostic workup is required?

       Patient Management Recommendations

       Level A recommendations

      None specified.

       Level B recommendations

      For patients who are at low risk for acute PE, use the PERC to exclude the diagnosis without further diagnostic testing.

       Level C recommendations

      None specified.
      Potential Benefits of Implementing the Recommendations:
      • Reduced test-related complications (eg, contrast-induced nephropathy, contrast-related allergic reactions, contrast infiltrations, radiation exposure)
      • Reduced costs associated with less diagnostic testing
      • Reduced time in the ED associated with less diagnostic testing
      • Better use of health care resources
      • Improved patient satisfaction as a result of more efficient evaluation
      Potential Harms of Implementing the Recommendations:
      • A small increase in the incidence of missed PE
      • Misapplication of the recommendation to individuals with intermediate or high pretest probability of PE
      Key words/phrases for literature searches: pulmonary embolism, acute pulmonary embolism, diagnosis, decision support techniques, clinical decision making, clinical decision support, clinical decision rule, evidence based medicine, hospital emergency service, risk assessment, rule-out, low-risk, and variations and combinations of the key words/phrases. Searches included January 1, 2006, to search date of April 22, 2016.
      Study Selection: Forty-seven articles were identified in this search. Nineteen relevant articles were selected from the search results for further methodological review and grading. Four Class II articles and 4 Class III articles were included for this critical question.
      During the past 2 decades, clinical prediction rules have been derived and validated to assist in determination of pretest probability and subsequent Bayesian decisionmaking for the evaluation of patients with suspected PE.
      • Wicki J.
      • Perneger T.V.
      • Junod A.F.
      • et al.
      Assessing clinical probability of pulmonary embolism in the emergency ward.
      • Le Gal G.
      • Righini M.
      • Roy P.-M.
      • et al.
      Prediction of pulmonary embolism in the emergency department: the revised Geneva score.
      • Klok F.A.
      • Mos I.C.
      • Nijkeuter M.
      • et al.
      Simplification of the revised Geneva score for assessing clinical probability of pulmonary embolism.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.
      • et al.
      Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer.
      • Kline J.A.
      • Nelson R.D.
      • Jackson R.E.
      • et al.
      Criteria for the safe use of D-dimer testing in emergency department patients with suspected pulmonary embolism: a multicenter US study.
      • Kline J.A.
      • Mitchell A.M.
      • Kabrhel C.
      • et al.
      Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
      Most have focused on identifying populations for appropriate use of a given diagnostic test (eg, the D-dimer).
      • Wicki J.
      • Perneger T.V.
      • Junod A.F.
      • et al.
      Assessing clinical probability of pulmonary embolism in the emergency ward.
      • Le Gal G.
      • Righini M.
      • Roy P.-M.
      • et al.
      Prediction of pulmonary embolism in the emergency department: the revised Geneva score.
      • Klok F.A.
      • Mos I.C.
      • Nijkeuter M.
      • et al.
      Simplification of the revised Geneva score for assessing clinical probability of pulmonary embolism.
      • Wells P.S.
      • Anderson D.R.
      • Rodger M.
      • et al.
      Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer.
      • Kline J.A.
      • Nelson R.D.
      • Jackson R.E.
      • et al.
      Criteria for the safe use of D-dimer testing in emergency department patients with suspected pulmonary embolism: a multicenter US study.
      In 2004, Kline et al
      • Kline J.A.
      • Mitchell A.M.
      • Kabrhel C.
      • et al.
      Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
      took a different approach by aiming to derive a clinical prediction rule that would be able to exclude the diagnosis of PE in low-risk patients without additional diagnostic testing. Conventionally, clinicians identify these low-risk patients by either clinical gestalt assessment (eg, pretest probability <15%) or a structured clinical prediction rule (eg, Wells score <2).
      • Kline J.A.
      Diagnosis and exclusion of pulmonary embolism.
      The derivation of the PERC was described in a Class II multicenter study
      • Kline J.A.
      • Mitchell A.M.
      • Kabrhel C.
      • et al.
      Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
      with 3,148 patients undergoing evaluation for PE. Twenty-one descriptive variables relevant to the diagnosis were prospectively collected and compared with a primary outcome of a composite criterion standard for the diagnosis of PE that included 90-day clinical follow-up. The overall prevalence of VTE was 11%. Logistic regression analysis was used to identify criteria that could predict a patient population estimated to have a prevalence of disease below 1.8%, at which point the diagnosis was considered reasonably excluded. Eight criteria were identified: younger than 50 years, pulse rate less than 100 beats/min, room air SaO2 greater than 94% (at sea level), no recent trauma or surgery, no unilateral leg swelling, no previous PE or DVT, no hormone use, and no hemoptysis. The authors proposed that when all 8 criteria are met in patients at low risk for PE, a patient could be considered PERC negative and that further diagnostic workup for PE, including a D-dimer test, would be unnecessary. Since its derivation, 3 Class II
      • Kline J.A.
      • Mitchell A.M.
      • Kabrhel C.
      • et al.
      Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
      • Kline J.A.
      • Courtney D.M.
      • Kabrhel C.
      • et al.
      Prospective multicenter evaluation of the pulmonary embolism rule-out criteria.
      • Hugli O.
      • Righini M.
      • Le Gal G.
      • et al.
      The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism.
      and 4 Class III
      • Bozarth A.L.
      • Bajaj N.
      • Wessling M.R.
      • et al.
      Evaluation of the pulmonary embolism rule-out criteria in a retrospective cohort at an urban academic hospital.
      • Crichlow A.
      • Cuker A.
      • Mills A.M.
      Overuse of computed tomography pulmonary angiography in the evaluation of patients with suspected pulmonary embolism in the emergency department.
      • Penaloza A.
      • Verschuren F.
      • Dambrine S.
      • et al.
      Performance of the Pulmonary Embolism Rule-out Criteria (the PERC rule) combined with low clinical probability in high prevalence population.
      • Wolf S.J.
      • McCubbin T.R.
      • Nordenholz K.E.
      • et al.
      Assessment of the pulmonary embolism rule-out criteria rule for evaluation of suspected pulmonary embolism in the emergency department.
      validation studies, along with 1 Class II meta-analysis
      • Singh B.
      • Parsaik A.K.
      • Agarwal D.
      • et al.
      Diagnostic accuracy of pulmonary embolism rule-out criteria: a systematic review and meta-analysis.
      have been published on the criteria’s performance. Data from these studies will be discussed as they relate to sample cohort pretest probability, which directly determines posttest probability after application of the criteria.

       PERC Performance in Low-Risk Cohorts

      As mentioned, the original study by Kline et al
      • Kline J.A.
      • Mitchell A.M.
      • Kabrhel C.
      • et al.
      Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
      derived the PERC in a low-pretest-probability cohort. This Class II study also included an independent validation cohort of 1,427 patients determined to be at low risk by clinical gestalt with an 8% prevalence of PE. Twenty-five percent of all patients were PERC negative, yielding a sensitivity, specificity, and negative likelihood ratio for the criteria of 96%, 27%, and 0.16, respectively. Therefore, with the overall 8% prevalence of PE as the pretest probability, it was estimated that the posttest probability for PE among the PERC-negative patients was 1.4%, which was below the a priori testing threshold. The authors concluded that in patients with low suspicion for PE who are PERC negative, the probability of PE is so low that further testing will not yield a favorable risk-benefit ratio.
      • Kline J.A.
      • Mitchell A.M.
      • Kabrhel C.
      • et al.
      Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
      In 2008, a second Class II validation study by the same author
      • Kline J.A.
      • Courtney D.M.
      • Kabrhel C.
      • et al.
      Prospective multicenter evaluation of the pulmonary embolism rule-out criteria.
      included 8,138 patients, of whom 66% were deemed to be at low pretest probability. The prevalence of VTE was 7% for the entire cohort and 3% for the low-risk cohort. The PERC performance was nearly identical to that of the original study, regardless of pretest probability.
      Three additional external validation studies with low-risk cohorts have also been published.
      • Hugli O.
      • Righini M.
      • Le Gal G.
      • et al.
      The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism.
      • Penaloza A.
      • Verschuren F.
      • Dambrine S.
      • et al.
      Performance of the Pulmonary Embolism Rule-out Criteria (the PERC rule) combined with low clinical probability in high prevalence population.
      • Wolf S.J.
      • McCubbin T.R.
      • Nordenholz K.E.
      • et al.
      Assessment of the pulmonary embolism rule-out criteria rule for evaluation of suspected pulmonary embolism in the emergency department.
      The first, a Class II study by Hugli et al
      • Hugli O.
      • Righini M.
      • Le Gal G.
      • et al.
      The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism.
      in 2011, is the only study to challenge the use of the PERC in low-risk patients. This retrospective study included 1,675 total patients, 35% of whom were at low risk. The prevalence of PE was 21% for the total cohort and 10% for the low-risk cohorts. In this study, the PERC performed considerably worse, yielding a sensitivity, specificity, and negative likelihood ratio of 79%, 33%, and 0.63, respectively. In their study, the posttest incidence of VTE in PERC-negative, low-risk patients was 6.4%. Besides the significantly higher baseline prevalence of disease, this European study had a lower proportion of patients in the overall cohort considered to be at low risk, and the PERC were applied retrospectively to the prospectively collected database. It is unclear whether these factors or some other element of regional practice played a role in the criteria’s poorer performance. In this study, when the PERC was applied to the entire cohort, regardless of previous probability, the PERC performed better than when applied to the low-risk cohort alone. Two Class III studies support the use of PERC, demonstrating 100% sensitivity in 459 low-risk patients with a combined prevalence of PE of 5.9%.
      • Penaloza A.
      • Verschuren F.
      • Dambrine S.
      • et al.
      Performance of the Pulmonary Embolism Rule-out Criteria (the PERC rule) combined with low clinical probability in high prevalence population.
      • Wolf S.J.
      • McCubbin T.R.
      • Nordenholz K.E.
      • et al.
      Assessment of the pulmonary embolism rule-out criteria rule for evaluation of suspected pulmonary embolism in the emergency department.
      Last, a 2012 Class II meta-analysis that included 13,885 low-risk patients with a 10% prevalence of PE found the PERC to be adequate to exclude the diagnosis of PE in a low-risk population.
      • Singh B.
      • Parsaik A.K.
      • Agarwal D.
      • et al.
      Diagnostic accuracy of pulmonary embolism rule-out criteria: a systematic review and meta-analysis.
      Their analysis included 8 patient cohorts that were not included in this clinical policy (3 with abstract data only,
      • Beam D.
      • Brewer K.
      • Kline J.A.
      Application of the pulmonary embolism rule-out criteria in a rural population.
      • Courtney D.M.
      • Pribaz J.R.
      • Senh A.C.
      Prospective evaluation of the pulmonary embolism rule-out criteria (PERC) rule: an 8-variable block rule to identify subjects at very low risk of pulmonary embolism.
      • Crichlow A.
      • Cuker A.
      • Matsuura A.C.
      • et al.
      Underuse of clinical decision rules and D-dimer testing in the evaluation of patients presenting to the emergency department with suspected venous thromboembolism.
      4 graded Class X,
      • Hogg K.
      • Dawson D.
      • Kline J.
      Application of pulmonary embolism rule-out criteria to the UK Manchester Investigation of Pulmonary Embolism Diagnosis (MIOPED) study cohort.
      • Righini M.
      • Le Gal G.
      • Perrier A.
      • et al.
      More on: clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
      • Dachs R.J.
      • Kulkarni D.
      • Higgins G.L.
      The pulmonary embolism rule-out criteria rule in a community hospital ED: a retrospective study of its potential utility.
      • Kline J.A.
      • Peterson C.E.
      • Steuerwald M.T.
      Prospective evaluation of real-time use of the pulmonary embolism rule-out criteria in an academic emergency department.
      and 1 nonapplicable cohort included in the original Kline et al
      • Kline J.A.
      • Mitchell A.M.
      • Kabrhel C.
      • et al.
      Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
      derivation study). The meta-analysis found a pooled sensitivity, specificity, and negative likelihood ratio of 97%, 23%, and 0.18, respectively. Thus, based on these results, for a patient with a pretest probability for PE estimated to be 10% who is determined to be PERC negative, the posttest probability for having PE would be 1.9%.

       PERC Performance in Undifferentiated Cohorts

      Although the PERC were not derived to exclude the diagnosis of PE in a population with an undifferentiated pretest probability for PE (ie, low, moderate, or high), several studies have looked at its performance in this context, with conflicting results. One Class II
      • Kline J.A.
      • Courtney D.M.
      • Kabrhel C.
      • et al.
      Prospective multicenter evaluation of the pulmonary embolism rule-out criteria.
      and 3 Class III
      • Bozarth A.L.
      • Bajaj N.
      • Wessling M.R.
      • et al.
      Evaluation of the pulmonary embolism rule-out criteria in a retrospective cohort at an urban academic hospital.
      • Crichlow A.
      • Cuker A.
      • Mills A.M.
      Overuse of computed tomography pulmonary angiography in the evaluation of patients with suspected pulmonary embolism in the emergency department.
      • Wolf S.J.
      • McCubbin T.R.
      • Nordenholz K.E.
      • et al.
      Assessment of the pulmonary embolism rule-out criteria rule for evaluation of suspected pulmonary embolism in the emergency department.
      studies support the use of PERC regardless of the pretest probability. Combined, these studies looked at 9,129 patients with a 6.9% prevalence of VTE, demonstrating negative likelihood ratios for PERC ranging from 0 to 0.26, with posttest incidence of VTE ranging from 0% to 1.2%.
      Two studies (1 Class II
      • Hugli O.
      • Righini M.
      • Le Gal G.
      • et al.
      The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism.
      and 1 Class III
      • Penaloza A.
      • Verschuren F.
      • Dambrine S.
      • et al.
      Performance of the Pulmonary Embolism Rule-out Criteria (the PERC rule) combined with low clinical probability in high prevalence population.
      ) demonstrated poorer PERC performance in patient populations with undifferentiated risk. Together, these studies enrolled 2,634 patients with suspected PE, 24.4% of whom ultimately received a diagnosis of VTE. Among these cohorts with higher risk for PE, the posttest probability in PERC-negative patients was 5.4%, which is a risk above the testing threshold and would require further diagnostic testing.
      Pooling data from any of these studies is difficult because of substantial heterogeneity. Table 1 summarizes data from each of these studies. Therefore, there is insufficient evidence to recommend using the PERC to exclude PE in a non–low-risk population.
      Table 1PERC performance.
      Study CohortsClassPretest ProbabilityNPE (%)PERC DeterminationPERC PerformancePosttest VTE (%) (95% CI)
      Sensitivity (95% CI), %Specificity (95% CI), %Negative LR (95% CI)
      Low-Risk Cohorts
      Kline et al
      • Kline J.A.
      • Mitchell A.M.
      • Kabrhel C.
      • et al.
      Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
      IILow1,427114 (8)Prospective96 (90-99)27 (25-30)0.16 (0.07-0.38)1.4 (0.4-3.2)
      Kline et al
      • Kline J.A.
      • Courtney D.M.
      • Kabrhel C.
      • et al.
      Prospective multicenter evaluation of the pulmonary embolism rule-out criteria.
      IILow5,425163 (3)Prospective97 (96-99)22 (21-23)0.12 (0.07-1.19)1.3 (0.8-1.9)
      Hugli et al
      • Hugli O.
      • Righini M.
      • Le Gal G.
      • et al.
      The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism.
      IILow58757 (10)Retrospective79 (67-88)33 (29-37)0.63 (0.04-1.06)6.4 (3.7-6.8)
      Wolf et al
      • Wolf S.J.
      • McCubbin T.R.
      • Nordenholz K.E.
      • et al.
      Assessment of the pulmonary embolism rule-out criteria rule for evaluation of suspected pulmonary embolism in the emergency department.
      IIILow601 (2)Retrospective100 (25-100)22 (12-35)0 (
      Undefined given 100% sensitivity
      )
      0 (0-24.7)
      Penaloza et al
      • Penaloza A.
      • Verschuren F.
      • Dambrine S.
      • et al.
      Performance of the Pulmonary Embolism Rule-out Criteria (the PERC rule) combined with low clinical probability in high prevalence population.
      IIILow39926 (7)Retrospective100 (99-100)9 (6-11)0 (
      Undefined given 100% sensitivity
      )
      0 (0-5)
      Undifferentiated-Risk Cohorts
      Kline et al
      • Kline J.A.
      • Courtney D.M.
      • Kabrhel C.
      • et al.
      Prospective multicenter evaluation of the pulmonary embolism rule-out criteria.
      IIAll8,138561 (7)Prospective96 (94-97)25 (24-26)0.17 (0.11-0.25)1.0 (0.6-1.6)
      Hugli et al
      • Hugli O.
      • Righini M.
      • Le Gal G.
      • et al.
      The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism.
      IIAll1,675357 (21)Retrospective97 (94-98)16 (14-18)0.21 (0.12-0.37)5.4 (3.1-9.3)
      Wolf et al
      • Wolf S.J.
      • McCubbin T.R.
      • Nordenholz K.E.
      • et al.
      Assessment of the pulmonary embolism rule-out criteria rule for evaluation of suspected pulmonary embolism in the emergency department.
      IIIAll12016 (12)Retrospective100 (79-100)16 (10-24)0 (
      Undefined given 100% sensitivity
      )
      0 (0-17.6)
      Crichlow et al
      • Crichlow A.
      • Cuker A.
      • Mills A.M.
      Overuse of computed tomography pulmonary angiography in the evaluation of patients with suspected pulmonary embolism in the emergency department.
      IIIAll15218 (12)Prospective100 (78-100)10 (6-17)0 (
      Undefined given 100% sensitivity
      )
      0 (0-23.2)
      Penaloza et al
      • Penaloza A.
      • Verschuren F.
      • Dambrine S.
      • et al.
      Performance of the Pulmonary Embolism Rule-out Criteria (the PERC rule) combined with low clinical probability in high prevalence population.
      IIIAll959286 (30)Retrospective99 (97-100)10 (8-13)0.13 (0.05-0.36)5.4 (1.7-12.5)
      Bozarth et al
      • Bozarth A.L.
      • Bajaj N.
      • Wessling M.R.
      • et al.
      Evaluation of the pulmonary embolism rule-out criteria in a retrospective cohort at an urban academic hospital.
      IIIAll71932 (5)Retrospective97 (94-100)12 (10-15)0.26 (0.04-1.82)1.2 (0-6.5)
      CI, confidence interval; LR, likelihood ratio; PE, pulmonary embolism; PERC, pulmonary embolism rule-out criteria; VTE, venous thromboembolism;
      Undefined given 100% sensitivity
      In summary, the existing literature supports the use of PERC to exclude PE in low-risk patients based on a moderate degree of certainty. However, these results are tempered by one study
      • Hugli O.
      • Righini M.
      • Le Gal G.
      • et al.
      The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism.
      with a point estimate greater than the commonly quoted threshold of 2.0% posttest prevalence. Additionally, there is insufficient evidence to support the use of PERC in higher-risk populations.

       Future Research

      Although evidence exists to support the use of PERC in low-risk patients with suspected PE, future research should focus on more accurately defining pretest probability risk cut offs and optimizing the diagnostic evaluation of PE in higher-risk subgroups.
      • 2.
        In adult patients with low to intermediate pretest probability for acute PE, does a negative age-adjusted D-dimer result identify a group of patients at very low risk for the diagnosis of PE for whom no additional diagnostic workup is required?

       Patient Management Recommendations

       Level A recommendations

      None specified.

       Level B recommendations

      In patients older than 50 years deemed to be low or intermediate risk for acute PE, clinicians may use a negative age-adjusted D-dimer
      For highly sensitive D-dimer assays using fibrin equivalent units (FEU) use a cutoff of age×10 μg/L; for highly sensitive D-dimer assays using D-dimer units (DDU), use a cutoff of age×5 μg/L.
      result to exclude the diagnosis of PE.

       Level C recommendations

      None specified.
      Potential Benefits of Implementing the Recommendations:
      • Reduced test-related complications (eg, contrast-induced nephropathy, contrast-related allergic reactions, contrast infiltrations, radiation exposure)
      • Reduced cost associated with less diagnostic testing
      • Reduced time in ED associated with less diagnostic testing
      • Better use of health care resources
      • Improved patient satisfaction as a result of more efficient evaluation
      Potential Harms of Implementing the Recommendations:
      • A small increased incidence of missed PE
      • Misapplication of the recommendation because of confusion with multiple D-dimer assay units
      Key words/phrases for literature searches: pulmonary embolism, acute pulmonary embolism, diagnosis, lung embolism, fibrin degradation product, D-dimer, fibrin fragment, probability, age-adjusted, sensitivity and specificity, emergency service, hospital, predictive value of tests, and variations and combinations of the key words/phrases. Searches included January 1, 2006, to search date of April 22, 2016.
      Study Selection: Fifty-nine articles were identified in this search. Forty-two relevant articles were selected from the search results for further methodological review and grading. Three Class II articles and 7 Class III articles were included for this critical question.
      The diagnosis of PE poses a special challenge in the elderly, given that its prevalence increases with age,
      • Oger E.
      Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group.
      as does the frequency of comorbid conditions that can present with similar signs and symptoms. Although the accuracy and clinical utility of prediction rules remain good in this population,
      • Righini M.
      • Le Gal G.
      • Perrier A.
      • et al.
      Effect of age on the assessment of clinical probability of pulmonary embolism by prediction rules.
      • Di Marca S.
      • Cilia C.
      • Campagna A.
      • et al.
      Comparison of Wells and revised Geneva rule to assess pretest probability of pulmonary embolism in high-risk hospitalized elderly adults.
      there is an age-dependent increase in D-dimer levels
      • Haase C.
      • Joergensen M.
      • Ellervik C.
      • et al.
      Age- and sex-dependent reference intervals for D-dimer: evidence for a marked increase by age.
      that results in a decline in the specificity of D-dimer testing in the elderly when a conventional fixed cutoff is used. This can lead to high rates of unnecessary imaging in this group.
      Raising the D-dimer threshold in older patients who are at nonhigh risk of VTE has been studied as a strategy to improve workup efficiency. Nonhigh risk refers to a low or intermediate pretest probability, or “PE unlikely” using a validated clinical prediction rule. Most of the studies included in our systematic review of the literature used a D-dimer cutoff based on the patient’s age in years (age×10 μg/L) for patients older than 50 years (unless otherwise specified); however, other strategies have been studied such as using a cutoff that increases by decade, or simply applying a single higher threshold to patients older than 50 years or 70 years. All but one included study used one or more high-sensitivity D-dimer assays (eg, VIDAS, Tinaquant, STA-Liatest, Innovance, and D-dimer HS), which generally use a conventional cutoff of FEU at 500 μg/L.
      • Righini M.
      • Van Es J.
      • Den Exter P.L.
      • et al.
      Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism. The ADJUST-PE study.
      • van Es N.
      • van der Hulle T.
      • van Es J.
      • et al.
      Wells rule and D-dimer testing to rule out pulmonary embolism. A systematic review and individual-patient data meta-analysis.
      • Flores J.
      • Garcia de Tena J.
      • Galipienzo J.
      • et al.
      Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis.
      • Douma R.A.
      • le Gal G.
      • Söhne M.D.
      • et al.
      Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.
      • van Es J.
      • Mos I.
      • Douma R.
      • et al.
      The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded.
      • Sharp A.L.
      • Vinson D.R.
      • Alamshaw F.
      • et al.
      An age-adjusted D-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications.
      • Gupta A.
      • Raja A.S.
      • Ip I.K.
      • et al.
      Assessing 2 D-dimer age-adjustment strategies to optimize computed tomographic use in ED evaluation of pulmonary embolism.
      • Friz H.P.
      • Pasciuti L.
      • Meloni D.F.
      • et al.
      A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients.
      • Kline J.A.
      • Hogg M.M.
      • Courtney D.M.
      • et al.
      D-dimer threshold increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary computerized tomographic pulmonary angiography.
      One study used the HemosIL D-dimer assay, which reported results in DDU that are equivalent to approximately half of an FEU, and the formula for age adjustment was adjusted accordingly (age×5 μg/L).

      Jaconelli T, Eragat M, Crane S. Can an age-adjusted D-dimer level be adopted in managing venous thromboembolism in the emergency department? A retrospective cohort study. Eur J Emerg Med. https://doi.org/10.1097/MEJ.0000000000000448.

      The primary concern when using an age-adjusted D-dimer cutoff is whether increasing the threshold increases the risk of missed PEs. This measure was expressed as sensitivity in some studies, yet was variably reported as the number of false negatives or “failure rate” in others. In this section, we use the analogous term “miss rate,” defined here as the proportion of patients with a negative D-dimer result (cutoff defined in each study) who ultimately received a diagnosis of PE.
      The practical consideration when using an age-adjusted D-dimer cutoff is how much it reduces the need for additional imaging. Many studies reported the “clinical usefulness” or “efficiency” of the test (ie, the proportion of patients with negative D-dimer test results), although this does not directly reflect whether the negative results were true or false.
      Several other societies have reviewed the issue of age-adjusted D-dimers in their guidelines. The best practice advice put forth by the American College of Physicians recommends using age-adjusted D-dimer thresholds in patients older than 50 years, and not ordering imaging if the D-dimer level is below the cutoff.
      • Raja A.S.
      • Greenberg J.O.
      • Qaseem A.
      • et al.
      Clinical Guidelines Committee of the American College of Physicians
      Evaluation of patients with suspected acute pulmonary embolism: best practice advice from the Clinical Guidelines Committee of the American College of Physicians.
      The 2014 European Society of Cardiology guidelines on the diagnosis and management of PE discussed, but did not formally endorse, the use of age-adjusted D-dimers.
      • Konstantinides S.V.
      • Torbicki A.
      • Agnelli G.
      • et al.
      Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)
      2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism.
      A majority of the studies included in this systematic review were conducted in Europe, where a higher prevalence of PE was reported compared with most study populations in the United States, thus limiting applicability to the ED patient population in the United States.

       Safety of the Age-Adjusted D-dimer Strategy (Table 2)

      Overall, the 3 Class II studies
      • Righini M.
      • Van Es J.
      • Den Exter P.L.
      • et al.
      Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism. The ADJUST-PE study.
      • van Es N.
      • van der Hulle T.
      • van Es J.
      • et al.
      Wells rule and D-dimer testing to rule out pulmonary embolism. A systematic review and individual-patient data meta-analysis.
      • Flores J.
      • Garcia de Tena J.
      • Galipienzo J.
      • et al.
      Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis.
      found that the miss rate of the age-adjusted D-dimer was similar to a conventional D-dimer cutoff, and that the sensitivities were similar. The prospective study by Righini et al
      • Righini M.
      • Van Es J.
      • Den Exter P.L.
      • et al.
      Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism. The ADJUST-PE study.
      took place at multiple centers in Europe and included 3,324 ED patients with a 19% overall prevalence of PE; 87% were at nonhigh risk, and if the D-dimer result was negative, these patients were discharged without additional testing and without anticoagulation. The 3-month risk of missed (nonfatal) PE was 1 among 810 patients with a negative conventional D-dimer result (0.1%). There was 1 additional missed PE among the 331 patients who had a negative D-dimer result, using the age-adjusted D-dimer cutoff, for a total of 2 missed (nonfatal) PEs among 1,141 patients (0.2%).
      Table 2D-dimer performance in VTE patients older than 50 years using a CDD versus AADD.
      StudyClassCPRPTPAADD

      cutoff (μg/L)
      CDD Sensitivity (%; 95% CI)AADD Sensitivity (%; 95% CI)CDD Miss Rate

      (%; 95% CI)
      AADD Miss Rate

      (%; 95% CI)
      % Cohort With Negative CDD (95% CI)% Cohort With Negative AADD (95% CI)
      Righini et al
      • Righini M.
      • Van Es J.
      • Den Exter P.L.
      • et al.
      Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism. The ADJUST-PE study.
      Multiple CPRs were used; for simplicity, only results for Wells are presented.
      IIsRGS or WellsNon-high or unlikelyAge×10
      D-dimer value reported in FEUs.
      NRNR1/810 (0.1; 0-0.7)2/1,141 (0.2; 0-0.6)28 (27-30)40 (38-42)
      Flores et al
      • Flores J.
      • Garcia de Tena J.
      • Galipienzo J.
      • et al.
      Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis.
      IIWellsNon-highAge×10
      D-dimer value reported in FEUs.
      100 (94-100)100 (94-100)0/92 (0; 0-3.9)0/121 (0; 0-3.0)28 (23-33)37 (32-42)
      van Es et al
      • van Es N.
      • van der Hulle T.
      • van Es J.
      • et al.
      Wells rule and D-dimer testing to rule out pulmonary embolism. A systematic review and individual-patient data meta-analysis.
      IIWellsUnlikelyAge×10
      D-dimer value reported in FEUs.
      99

      (99-100)
      99

      (98-99)
      13/2,035

      (0.7; 0.4-1.1)
      22/2,369

      (0.9; 0.6-1.5)
      28

      (21-37)
      33

      (25-42)
      van Es et al
      • van Es J.
      • Mos I.
      • Douma R.
      • et al.
      The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded.
      Multiple CPRs were used; for simplicity, only results for Wells are presented.
      IIIWellsUnlikelyAge×10
      D-dimer value reported in FEUs.
      NRNR1/60

      (1.7; 0-8.9)
      2/92

      (2.2; 0-7.6)
      15

      (11-18)
      22

      (18-26)
      Gupta et al
      • Gupta A.
      • Raja A.S.
      • Ip I.K.
      • et al.
      Assessing 2 D-dimer age-adjustment strategies to optimize computed tomographic use in ED evaluation of pulmonary embolism.
      IIINRAnyAge×10
      D-dimer value reported in FEUs.
      100

      (94-100)
      97

      (90-100)
      0/72

      (0; 0-5.0)
      2/165

      (1.2; 0.1-4.3)
      7

      (7-9)
      16

      (14-19)
      Friz et al
      • Friz H.P.
      • Pasciuti L.
      • Meloni D.F.
      • et al.
      A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients.
      IIINRAnyAge×10
      D-dimer value reported in FEUs.
      100

      (97-100)
      98

      (94-100)
      0/8

      (0; 0-36.9)
      2/28

      (7.1; 0.9-23.5)
      2

      (1-3)
      6

      (4-8)
      Jaconelli et al

      Jaconelli T, Eragat M, Crane S. Can an age-adjusted D-dimer level be adopted in managing venous thromboembolism in the emergency department? A retrospective cohort study. Eur J Emerg Med. https://doi.org/10.1097/MEJ.0000000000000448.

      IIIWellsUnlikelyAge×5
      D-dimer value reported in DDUs;
      95

      (86-99)
      95

      (86-99)
      3/859

      (0.3; 0.1-1.0)
      3/989

      (0.3; 0.1-0.9)
      65

      (62-68)
      75

      (72-77)
      Sharp et al
      • Sharp A.L.
      • Vinson D.R.
      • Alamshaw F.
      • et al.
      An age-adjusted D-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications.
      IIINRAnyAge×10
      D-dimer value reported in FEUs.
      98

      (96-99)
      93

      (90-95)
      10/16,660

      (0.1; 0-0.1)
      36/19,584

      (0.2; 0.1-0.3)
      54

      (53-54)
      63

      (62-64)
      Douma et al
      • Douma R.A.
      • le Gal G.
      • Söhne M.D.
      • et al.
      Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.
      IIIWellsUnlikelyAge×10
      D-dimer value reported in FEUs.
      NRNR2/983

      (0.2; 0.1-0.7)
      7/1,093

      (0.6; 0.3-1.3)
      46

      (43-48)
      51

      (49-53)
      Douma et al
      • Douma R.A.
      • le Gal G.
      • Söhne M.D.
      • et al.
      Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.
      IIIRGSNon-highAge×10
      D-dimer value reported in FEUs.
      NRNR0/561

      (0; 0.0-0.7)
      2/663

      (0.3; 0.1-1.1)
      34

      (32-37)
      40

      (38-43)
      Sharp et al
      • Sharp A.L.
      • Vinson D.R.
      • Alamshaw F.
      • et al.
      An age-adjusted D-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications.
      IIINRAny1,000
      D-dimer value reported in FEUs.
      98

      (96-99)
      84

      (81-87)
      10/16,660

      (0.1; 0.0-0.1)
      80/23,146

      (0.3; 0.3-0.4)
      54

      (53-54)
      74

      (74-75)
      Friz et al
      • Friz H.P.
      • Pasciuti L.
      • Meloni D.F.
      • et al.
      A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients.
      IIINRAny1,000
      D-dimer value reported in FEUs.
      100

      (97-100)
      96

      (91-99)
      0/8

      (0; 0-36.9)
      4/61

      (6.6; 1.8-15.9)
      2

      (1-3)
      13

      (10-16)
      Kline et al
      • Kline J.A.
      • Hogg M.M.
      • Courtney D.M.
      • et al.
      D-dimer threshold increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary computerized tomographic pulmonary angiography.
      Multiple CPRs were used; for simplicity, only results for Wells are presented.
      Applied AADD to patients older than 70 years.
      IIIsRGS or WellsAny1,000
      D-dimer value reported in FEUs.
      94

      (88-97)
      92

      (86-96)
      8/152

      (5.3; 2-10.1)
      10/185

      (5.4; 2.6-9.7)
      22

      (19-26)
      27

      (24-31)
      AADD, age-adjusted D-dimer; CDD, conventional D-dimer; CI, confidence interval; CPR, clinical prediction rule; NR, not reported; PTP, pretest probability; RGS, revised Geneva score; sRGS, simplified revised Geneva score.
      Multiple CPRs were used; for simplicity, only results for Wells are presented.
      D-dimer value reported in FEUs.
      D-dimer value reported in DDUs;
      § Applied AADD to patients older than 70 years.
      Van Es et al
      • van Es N.
      • van der Hulle T.
      • van Es J.
      • et al.
      Wells rule and D-dimer testing to rule out pulmonary embolism. A systematic review and individual-patient data meta-analysis.
      conducted a meta-analysis using patient-level data from 6 prospective studies (including data from the Righini et al study
      • Righini M.
      • Van Es J.
      • Den Exter P.L.
      • et al.
      Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism. The ADJUST-PE study.
      ) that included 7,268 patients with a 22% overall prevalence of PE. This meta-analysis found that among patients with “PE unlikely” based on the Wells criteria and a negative conventional D-dimer result, the incidence of symptomatic VTE during a 3-month follow-up period was 0.7%, and there were no fatal events. In comparison, the miss rate with the age-adjusted D-dimer was 0.9%, with 1 fatal event. The sensitivity of both the conventional D-dimer and age-adjusted D-dimer cutoffs was 99%.
      Flores et al
      • Flores J.
      • Garcia de Tena J.
      • Galipienzo J.
      • et al.
      Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis.
      conducted a study of 362 ED patients in Spain; all patients had imaging, with the D-dimer level tested for research purposes, and the prevalence of PE in this population was 27%. Among the 331 non–high-risk patients by Wells criteria, there were 0 missed PEs with either the conventional D-dimer or the age-adjusted D-dimer, thus yielding a 100% sensitivity for both the conventional D-dimer and age-adjusted D-dimer cutoffs.
      Additionally, a majority of the 5 Class III studies found a low risk of missed PEs and a high sensitivity with the age-adjusted D-dimer cutoff.
      • Douma R.A.
      • le Gal G.
      • Söhne M.D.
      • et al.
      Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.
      • van Es J.
      • Mos I.
      • Douma R.
      • et al.
      The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded.
      • Sharp A.L.
      • Vinson D.R.
      • Alamshaw F.
      • et al.
      An age-adjusted D-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications.
      • Gupta A.
      • Raja A.S.
      • Ip I.K.
      • et al.
      Assessing 2 D-dimer age-adjustment strategies to optimize computed tomographic use in ED evaluation of pulmonary embolism.
      • Friz H.P.
      • Pasciuti L.
      • Meloni D.F.
      • et al.
      A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients.
      Douma et
      • Douma R.A.
      • le Gal G.
      • Söhne M.D.
      • et al.
      Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.
      derived the age-adjusted formula and then validated it in 2 retrospective cohorts, showing miss rates of 0.3% and 0.6% with the age-adjusted D-dimer cutoff versus miss rates of 0.0% and 0.2% with the conventional D-dimer cutoff. Van Es et al
      • van Es J.
      • Mos I.
      • Douma R.
      • et al.
      The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded.
      compared the age-adjusted D-dimer with the conventional D-dimer cutoff, using a number of well-validated clinical prediction rules. For non–high-risk patients, they reported age-adjusted D-dimer miss rates ranging from 2.2% to 2.5% compared with conventional D-dimer miss rates of 1.7% to 1.8%. The other 3 studies looked at cohorts of patients with suspected PE who had D-dimer tests, presumably not exclusively nonhigh risk, but the pretest probability was not provided.
      • Sharp A.L.
      • Vinson D.R.
      • Alamshaw F.
      • et al.
      An age-adjusted D-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications.
      • Gupta A.
      • Raja A.S.
      • Ip I.K.
      • et al.
      Assessing 2 D-dimer age-adjustment strategies to optimize computed tomographic use in ED evaluation of pulmonary embolism.
      • Friz H.P.
      • Pasciuti L.
      • Meloni D.F.
      • et al.
      A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients.
      Sharp et al
      • Sharp A.L.
      • Vinson D.R.
      • Alamshaw F.
      • et al.
      An age-adjusted D-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications.
      analyzed one such ED cohort in the United States with a low prevalence of PE and found a miss rate of 0.1% with the conventional D-dimer cutoff, 0.2% for the age-adjusted D-dimer cutoff, and 0.3% when applying a threshold of 1,000 μg/L. Gupta et al
      • Gupta A.
      • Raja A.S.
      • Ip I.K.
      • et al.
      Assessing 2 D-dimer age-adjustment strategies to optimize computed tomographic use in ED evaluation of pulmonary embolism.
      applied 2 different age-adjusted strategies to an ED cohort in the United States (PE prevalence of 7%) and reported similar sensitivities for both the yearly cutoff (97.4%) and a decadal cutoff (98.7%); the sensitivity for the conventional D-dimer cutoff in this cohort was 100%. Finally, Friz et al
      • Friz H.P.
      • Pasciuti L.
      • Meloni D.F.
      • et al.
      A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients.
      studied a cohort in Italy who all had D-dimer tests and CTs as part of standard practice for suspected PE in their ED, and in this higher-risk population (PE prevalence of 23%) the sensitivity was 98% based on the yearly age-adjusted D-dimer formula and 96% for a cutoff of 1,000 μg/L, compared with 100% for conventional D-dimer.

       Clinical Usefulness of Using the Age-Adjusted D-dimer Cutoff (Table 2)

      The 3 Class II studies found a modest increase (ranging from 5% to 12%) in the proportion of non–high-risk patients having a negative D-dimer result, using an age-adjusted cutoff versus a conventional cutoff.
      • Righini M.
      • Van Es J.
      • Den Exter P.L.
      • et al.
      Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism. The ADJUST-PE study.
      • van Es N.
      • van der Hulle T.
      • van Es J.
      • et al.
      Wells rule and D-dimer testing to rule out pulmonary embolism. A systematic review and individual-patient data meta-analysis.
      • Flores J.
      • Garcia de Tena J.
      • Galipienzo J.
      • et al.
      Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis.
      Righini et al
      • Righini M.
      • Van Es J.
      • Den Exter P.L.
      • et al.
      Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism. The ADJUST-PE study.
      showed a 12% increase in the proportion of patients with negative D-dimer results, using the age-adjusted D-dimer versus the conventional D-dimer, from 28% to 40%. Van Es et al
      • van Es N.
      • van der Hulle T.
      • van Es J.
      • et al.
      Wells rule and D-dimer testing to rule out pulmonary embolism. A systematic review and individual-patient data meta-analysis.
      found an increase from 28% using the conventional D-dimer to 33% when the age-adjusted D-dimer was applied to a PE-unlikely group. Flores et al
      • Flores J.
      • Garcia de Tena J.
      • Galipienzo J.
      • et al.
      Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis.
      reported an increase in the proportion of patients with a negative D-dimer result from 28% to 37%, using the conventional D-dimer and age-adjusted D-dimer, respectively, and an improvement in specificity from 36% to 47%.
      The results of 5 Class III studies were similar.
      • Douma R.A.
      • le Gal G.
      • Söhne M.D.
      • et al.
      Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.
      • van Es J.
      • Mos I.
      • Douma R.
      • et al.
      The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded.
      • Sharp A.L.
      • Vinson D.R.
      • Alamshaw F.
      • et al.
      An age-adjusted D-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications.
      • Gupta A.
      • Raja A.S.
      • Ip I.K.
      • et al.
      Assessing 2 D-dimer age-adjustment strategies to optimize computed tomographic use in ED evaluation of pulmonary embolism.
      • Friz H.P.
      • Pasciuti L.
      • Meloni D.F.
      • et al.
      A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients.
      Douma et al,
      • Douma R.A.
      • le Gal G.
      • Söhne M.D.
      • et al.
      Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.
      in 2 validation sets, found an increase in the proportion of patients with negative D-dimer results from 46% to 51% and from 34% to 40% with the age-adjusted D-dimer strategy. Van Es et al
      • van Es J.
      • Mos I.
      • Douma R.
      • et al.
      The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded.
      separated the results by the clinical decision rule that was used and reported a 4% to 7% increase in the proportion of patients with a negative age-adjusted D-dimer result when using the Wells criteria, simplified Wells, RGS, or simplified RGS. In the study by Sharp et al,
      • Sharp A.L.
      • Vinson D.R.
      • Alamshaw F.
      • et al.
      An age-adjusted D-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications.
      the proportion of patients with a negative D-dimer result increased from 54% with the conventional D-dimer to 63% with the yearly age-adjusted D-dimer. Gupta et a
      • Gupta A.
      • Raja A.S.
      • Ip I.K.
      • et al.
      Assessing 2 D-dimer age-adjustment strategies to optimize computed tomographic use in ED evaluation of pulmonary embolism.
      found an increase in specificity from 7% to 14% with the decadal age-adjusted D-dimer, and to 17% with the yearly age-adjusted D-dimer. Friz et al
      • Friz H.P.
      • Pasciuti L.
      • Meloni D.F.
      • et al.
      A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients.
      reported a small increase, from 2% to 6%, with the yearly age-adjusted D-dimer formula, and from 2% to 13% with a cutoff of 1,000 μg/L.

       Performance of the Age-Adjusted D-dimer Strategy in Geriatric Subgroups

      A number of the studies discussed above also reported data for older subgroups of patients, in which the clinical usefulness of the age-adjusted D-dimer strategy appears greater. In the Class II study by Righini et al,
      • Righini M.
      • Van Es J.
      • Den Exter P.L.
      • et al.
      Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism. The ADJUST-PE study.
      the proportion of non–high-risk patients older than 75 years and with a negative conventional D-dimer result was only 6% (95% confidence interval [CI] 5% to 9%) and increased to 30% (95% CI 26% to 33%) with the age-adjusted D-dimer, with 0 missed PEs (95% CI 0% to 2%). The Class II study by van Es et al
      • van Es N.
      • van der Hulle T.
      • van Es J.
      • et al.
      Wells rule and D-dimer testing to rule out pulmonary embolism. A systematic review and individual-patient data meta-analysis.
      also reported an increase in the proportion of PE-unlikely patients older than 75 years and with a negative D-dimer result from 8% to 20% when using the age-adjusted D-dimer cutoff, with a concomitant increase in the miss rate from 0% to 2.1% (95% CI 1% to 6%). The Class III study by van Es et al
      • van Es J.
      • Mos I.
      • Douma R.
      • et al.
      The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded.
      found an increase in the proportion of patients with a negative D-dimer result, using conventional D-dimer versus age-adjusted D-dimer, of 6% to 21% using the Wells criteria, 5% to 17% with the simplified Wells, and 3% to 12% with the RGS or simplified RGS for patients older than 70 years. The Class III study by Friz et al
      • Friz H.P.
      • Pasciuti L.
      • Meloni D.F.
      • et al.
      A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients.
      looked at the subgroup of patients older than 80 years and found that the sensitivity of the D-dimer with the age-adjusted D-dimer was maintained at 100% (95% CI 91% to 100%) and the proportion of patients with a negative D-dimer result increased from 0% to 5% compared with the conventional D-dimer. In the oldest subgroup (>80 years), Douma et al
      • Douma R.A.
      • le Gal G.
      • Söhne M.D.
      • et al.
      Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.
      also found an increase in the proportion of patients with a negative D-dimer result, using age-adjusted D-dimer versus conventional D-dimer (from 9% to 21% in one validation set and from 15% to 29% in a second validation set), with similar miss rates, 2% (95% CI 0% to 11%) and 0% (95% CI 0% to 7%), respectively.
      In a Class III study, Kline et al
      • Kline J.A.
      • Hogg M.M.
      • Courtney D.M.
      • et al.
      D-dimer threshold increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary computerized tomographic pulmonary angiography.
      calculated the performance of a fixed cutoff of 1,000 μg/L in an ED cohort in the United States. Using a cutoff of 1,000 μg/L for patients older than 70 years yielded a sensitivity of 92% compared with 94% for a threshold of 500 μg/L among all age groups. These authors noted that of the 10 missed PEs using the higher threshold, 9 were subsegmental. However, using this strategy increased the specificity by only 6% (ie, from 26% to 32%).

       Assays That Use a Conventional D-dimer Cutoff Other Than 500 μg/L

      One Class III study

      Jaconelli T, Eragat M, Crane S. Can an age-adjusted D-dimer level be adopted in managing venous thromboembolism in the emergency department? A retrospective cohort study. Eur J Emerg Med. https://doi.org/10.1097/MEJ.0000000000000448.

      looked at whether the yearly age-adjusted strategy could be adapted to a setting that used the HemosIL-HS assay, reporting results using a DDU, with a manufacturer-recommended cutoff of 230 ng/mL. Quantitative D-dimer assay results are reported as either the concentration of DDU or as FEU, depending on the calibration method for the assay. The 2 numeric values are easily convertible because the mass of one FEU equals approximately half of one DDU (ie,1 FEU=2×DDU). For simplicity, this study compared a standard cutoff of 250 ng/mL with an age-adjusted formula of age×5 ng/mL for patients older than 50 years. This study included patients with nonhigh pretest probability for DVT and PE and found that specificity improved from 68% to 78%. There were no additional missed PEs.
      In summary, using a strategy of adjusting the D-dimer for age modestly increases the proportion of patients with a negative D-dimer result, which may reduce the need for advanced imaging in approximately 5% to 10% of patients, without a significant increase in missed cases of PE.

       Future Research

      Although evidence exists to support the use of age-adjusted D-dimer results in the evaluation of non–high-risk patients with suspected PE, future research should focus on further defining the role of age-adjusted D-dimer in older subgroups (eg, >80 years).
      • 3.
        In adult patients with subsegmental PE, is it safe to withhold anticoagulation?

       Patient Management Recommendations

       Level A recommendations

      None specified.

       Level B recommendations

      None specified.

       Level C recommendations

      Given the lack of evidence, anticoagulation treatment decisions for patients with subsegmental PE without associated DVT should be guided by individual patient risk profiles and preferences. [Consensus recommendation]
      Potential Benefits of Implementing the Recommendations:
      • Reduced treatment-related complications (eg, major and minor medication-related bleeding, medication-related allergic reactions)
      • Reduced time and costs associated with less frequent follow-up visits
      • Better use of health care resources
      • Improved patient satisfaction as a result of more efficient patient care and shared decisionmaking
      Potential Harm of Implementing the Recommendations:
      • PE-related complications due to inaccurate assessment of individual patient risk profiles.
      Key words/phrases for literature searches: pulmonary embolism, venous thromboembolism, lung embolism, vein embolism, thromboembolism, venous thromboembolism, subsegmental, anticoagulation, decision making, anticoagulant agent, anticoagulants, diagnosis, treatment withdrawal, health status indicators, fibrin fibrinogen degradation products, emergency service, and variations and combinations of the key words/phrases. Searches included January 1, 2006, to search date of April 22, 2016.
      Study Selection: Seventeen articles were identified in this search. Nine relevant articles were selected from the search results for further methodological review and grading. Two Class III articles were included for this critical question.
      Anticoagulation is typically considered standard treatment for PE, regardless of size. However, with advances in imaging technology and increased awareness of PE, the incidence of the disease has increased while its resultant mortality has remained unchanged.
      • Carrier M.
      • Righini M.
      • Wells P.S.
      • et al.
      Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies.
      • Wiener R.S.
      • Schwartz L.M.
      • Woloshin S.
      When a test is too good: how CT pulmonary angiograms find pulmonary emboli that do not need to be found.
      Given the risk of anticoagulation, some have questioned whether it is beneficial for patients with subsegmental PE,
      • Kearon C.
      • Akl E.A.
      • Omelas J.
      • et al.
      Antithrombotic therapy for VTE disease. CHEST Guideline and Expert Panel report.
      • Yoo H.H.
      • Queluz T.H.
      • El Dib R.
      Anticoagulant treatment for subsegmental pulmonary embolism.
      which has a lower morbidity than segmental or more central PE.
      • Carrier M.
      • Righini M.
      • Wells P.S.
      • et al.
      Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies.
      In addition, the distinction between isolated and nonisolated subsegmental PE is an important one. Isolated subsegmental PEs refer to those without an associated DVT, whereas nonisolated subsegmental PEs are those with an associated DVT; the latter are typically anticoagulated because of the DVT in and of themselves. In 2016, a Cochrane review on this topic found no credible evidence to evaluate whether anticoagulation is useful in patients with isolated subsegmental PE; however, this systematic review did not consider nonrandomized or cohort studies for inclusion.
      • Yoo H.H.
      • Queluz T.H.
      • El Dib R.
      Anticoagulant treatment for subsegmental pulmonary embolism.
      Our systematic review of the literature similarly found no Class I or II studies; however, 2 Class III studies
      • den Exter P.L.
      • van Es J.
      • Klok F.A.
      • et al.
      Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism.
      • Donato A.A.
      • Khoche S.
      • Santora J.
      • et al.
      Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography.
      were identified evaluating the effectiveness of anticoagulation therapy for patients with isolated subsegmental PE.
      A Class III study by den Exter et al
      • den Exter P.L.
      • van Es J.
      • Klok F.A.
      • et al.
      Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism.
      compared outcomes for patients with subsegmental PE with those with larger PEs. Although all patients enrolled received anticoagulation, their results suggest that patients with subsegmental PE have risks of recurrent VTE similar to those of patients with larger PEs at 3-month follow-up (3.6% versus 2.5%, respectively). However, this study’s applicability to the critical question was limited by the fact that all subjects enrolled were not confirmed to have “isolated” subsegmental PE (ie, all subjects did not undergo extremity ultrasonography or another imaging modality to rule out concomitant DVT). The other Class III study by Donato et al
      • Donato A.A.
      • Khoche S.
      • Santora J.
      • et al.
      Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography.
      included a total of 22 patients with confirmed, isolated subsegmental PE who did not receive anticoagulation; at 3-month follow-up, none had a recurrent VTE. In 20 of the 22 untreated patients, duplex ultrasonography of the lower extremities was found to be negative before the decision to not anticoagulate was made. This study also reported on the outcomes of 71 patients with isolated subsegmental PE who received anticoagulation; 1 of these patients had a recurrent (nonfatal) PE, but 8 experienced hemorrhage (5 major and 3 minor).
      • Donato A.A.
      • Khoche S.
      • Santora J.
      • et al.
      Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography.

       Future Research

      Given the lack of evidence on the prognosis and management of patients with isolated subsegmental PE, prospective randomized trials assessing the benefits and harms of anticoagulation are required. This information can then be used to inform shared decisionmaking between provider and patient.
      • 4.
        In adult patients diagnosed with acute PE, is initiation of anticoagulation and discharge from the ED safe?

       Patient Management Recommendations

       Level A recommendations

      None specified.

       Level B recommendations

      None specified.

       Level C recommendations

      Selected patients with acute PE who are at low risk for adverse outcomes as determined by PESI, simplified PESI (sPESI), or the Hestia criteria may be safely discharged from the ED on anticoagulation, with close outpatient follow-up.
      Potential Benefits of Implementing the Recommendations:
      • Reduced inpatient treatment-related complications (eg, hospital-acquired infections)
      • Reduced cost compared with inpatient patient care
      • Reduced hospital inpatient crowding
      • Reduced time associated with treatment follow-up
      • Better use of health care resources
      • Improved patient satisfaction as a result of more efficient patient care and the ability to be treated at home
      Potential Harms of Implementing the Recommendations:
      • Increased patient and provider anxiety with outpatient management of a potentially serious disease process
      • Delay in evaluation and management of any change in clinical condition, resulting from the need to return to the ED or a health care setting for evaluation and management
      Key words/phrases for literature searches: pulmonary embolism, acute pulmonary embolism, venous embolism, venous thromboembolism, thromboembolism, anticoagulants, anticoagulation, outpatients, patient discharge, home care services, outpatient, home treatment, discharge, risk factors, Hestia, sPESI, decision support techniques, patient selection, ambulatory care, risk assessment, time factors, treatment outcome, severity of illness, and variations and combinations of the key words/phrases. Searches included January 1, 2006, to search date of April 22, 2016.
      Study Selection: Ninety-five articles were identified in this search. Twenty-four relevant articles were selected from the search results for further methodological review and grading. Two Class II and 7 Class III articles were included for this critical question.
      Given the mortality historically associated with PE, patients have traditionally been hospitalized for monitoring and parenteral anticoagulant therapy.
      • den Exter P.L.
      • Zondag W.
      • Klok F.A.
      • et al.
      for the Vesta Study Investigators
      Efficacy and safety of outpatient treatment based on the Hestia clinical decision rule with or without N-terminal pro-brain natriuretic peptide testing in patients with acute pulmonary embolism: a randomized clinical 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.
      With the development of low-molecular-weight heparins (LMWH) that can be administered once or twice daily at home, protocols have been established allowing for safe outpatient treatment of patients with uncomplicated DVT.
      • den Exter P.L.
      • Zondag W.
      • Klok F.A.
      • et al.
      for the Vesta Study Investigators
      Efficacy and safety of outpatient treatment based on the Hestia clinical decision rule with or without N-terminal pro-brain natriuretic peptide testing in patients with acute pulmonary embolism: a randomized clinical trial.
      More recently, NOACs (eg, rivaroxaban, apixaban, dabigatran, edoxaban) have been approved for the treatment of both DVT and PE after studies demonstrated that this regimen was noninferior to traditional treatment with heparin and a VKA.
      More than 95% of patients who ultimately receive a diagnosis of acute PE are “hemodynamically stable” at presentation with an associated mortality of 1% to 15%.
      • Barco S.
      • Lankeit M.
      • Binder H.
      • et al.
      Home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban. Rationale and design of the HoT-PE Trial.
      • Yoo H.H.
      • Queluz T.H.
      • El Dib R.
      Outpatient versus inpatient treatment for acute pulmonary embolism.
      The availability of newer anticoagulation agents (eg, NOACs) that are equally effective, more easily administered, and do not require laboratory monitoring has led to efforts aimed at treating low-risk patients with newly diagnosed PE as outpatients who can be directly discharged from the ED.
      Multiple investigators have combined specific criteria into clinical prediction rules to identify which patients receiving a diagnosis of acute PE are at low risk for adverse outcomes.
      • den Exter P.L.
      • Zondag W.
      • Klok F.A.
      • et al.
      for the Vesta Study Investigators
      Efficacy and safety of outpatient treatment based on the Hestia clinical decision rule with or without N-terminal pro-brain natriuretic peptide testing in patients with acute pulmonary embolism: a randomized clinical 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.
      • 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.
      • Erkens P.M.
      • Gandara E.
      • Wells P.
      • et al.
      Safety of outpatient treatment in acute pulmonary embolism.
      • Otero R.
      • Uresandi F.
      • Jiménez D.
      • et al.
      Home treatment in pulmonary embolism.
      • Davies C.W.
      • Wimperis J.
      • Green E.S.
      • et al.
      Early discharge of patients with pulmonary embolism: a two-phase observational study.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      on behalf of the Hestia Study Investigators
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia study.
      • Barra S.N.
      • Paiva L.
      • Providencia R.
      • et al.
      A review on state-of-the-art data regarding safe early discharge following admission for pulmonary embolism: what do we know?.
      • Beam D.M.
      • Kahler Z.P.
      • Kline J.A.
      Immediate discharge and home treatment with rivaroxaban of low-risk venous thromboembolism diagnosed in two US emergency departments: a one-year preplanned analysis.
      • Kline J.A.
      • Kahler Z.P.
      • Beam D.M.
      Outpatient treatment of low-risk venous thromboembolism with monotherapy oral anticoagulation: patient quality of life outcomes and clinician acceptance.
      Among these criteria, the PESI, sPESI, and Hestia criteria are the most well studied, with generalizability to the acute care setting of the ED. The PESI was initially developed to predict 30-day mortality, whereas the Hestia criteria were developed with the intention to help identify patients at lower risk of adverse outcomes. (Figures 1 and 2)
      PESI and sPESI.
      Tabled 1
      Prognostic VariablesPoints Assigned
      Demographics
      AgeAge, in y
      Male sex+10
      Comorbid conditions
      Cancer+30
      Heart failure+10
      Chronic lung disease+10
      Clinical findings
      Pulse >110 beats/min+20
      Systolic blood pressure <100 mm Hg+30
      Respiratory rate >30 breaths/min+20
      Temperature <36°C (<96.8°F)+20
      Altered mental status+60
      Arterial oxygen saturation <90%+20
      Risk Class*Total Point Score
      I<65
      II66–85
      III86–105
      IV106–125
      V>125
      *Risk Classes I and II are considered low risk.
      †A total point score for a given patient is obtained by summing the patient’s age in years and the points for each applicable prognostic variable.
      Reprinted with permission of the American Thoracic Society. Copyright ©2018 American Thoracic Society. 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.
      • Aujesky D.
      • Obrosky D.S.
      • Stone R.A.
      • et al.
      Derivation and validation of a prognostic model for pulmonary embolism.
      The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
      Simplified Pulmonary Embolism Severity Index
      Age >80 years?
      Cardiopulmonary co-morbidity?
      History of cancer?
      Arterial oxyhaemoglobin saturation level <90%?
      Systolic blood pressure <100 mm Hg?
      Pulse frequency ≥110 beats/min?
      If one of the items is present the patient is regarded as high risk.
      Reprinted with permission. Zondag W, den Exter PL, Crobach MJ, et al; on behalf of the HESTIA Study Investigators. Comparison of two methods for selection of out of hospital treatment in patients with acute pulmonary embolism. Thromb Haemost. 2013;109:47-52.
      • Zondag W.
      • den Exter P.L.
      • Crobach M.J.
      • et al.
      on behalf of the Hestia Study Investigators
      Comparison of two methods for selection of out of hospital treatment in patients with acute pulmonary embolism.
      Hestia criteria.
      Haemodynamically instable?*
      Thrombolysis or embolectomy necessary?
      High risk for bleeding?**
      Oxygen supply to maintain oxygen saturation >90% >24 h?
      Pulmonary embolism diagnosed during anticoagulant treatment?
      Intravenous pain medication >24 h?
      Medical or social reason for treatment in the hospital >24 h?
      Creatinine clearance of less than 30 mL/min?***
      Severe liver impairment****
      Pregnant?
      Documented history of heparin-induced thrombocytopenia?
      If one of the questions is answered with YES, the patient cannot be treated at home.
      *Include the following criteria, but are left to the discretion of the investigator: systolic blood pressure <100 mm Hg with heart rate >100 beats per minute; condition requiring admission to an intensive care unit.
      **Gastrointestinal bleeding in the preceding 14 days, recent stroke (less than 4 weeks ago), recent operation (less than 2 weeks ago), bleeding disorder or thrombocytopenia (platelet count <75×109/L), uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg).
      ***Calculated creatinine clearance according to the Cockroft-Gault formula.
      ****Left to the discretion of the physician.
      h, hour; mL, milliliter; mm Hg, millimeters of mercury; min, minute.
      Reprinted with permission. Zondag W, den Exter PL, Crobach MJ, et al; on behalf of the HESTIA Study Investigators. Comparison of two methods for selection of out of hospital treatment in patients with acute pulmonary embolism. Thromb Haemost. 2013;109:47-52.
      • Zondag W.
      • den Exter P.L.
      • Crobach M.J.
      • et al.
      on behalf of the Hestia Study Investigators
      Comparison of two methods for selection of out of hospital treatment in patients with acute pulmonary embolism.
      Although most studies included in our systematic review applied similar definitions and methodology, they varied in several important ways, such as the inclusion of asymptomatic patients with PE, recruitment of patients from settings outside of the ED such as an outpatient clinic or hospital, the application of exclusion criteria beyond those used to establish low risk, the proportion of patients with cancer, the anticoagulation regimen, the definition of “early discharge,” and the length of follow-up for adverse outcomes.
      For inpatients receiving traditional anticoagulation therapy, limited data exist on outcomes specific to low-risk subgroups. Two randomized controlled trials were identified that assessed outcomes of low-risk patients admitted to the hospital and treated with traditional anticoagulation for 90 days.
      • 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.
      • Otero R.
      • Uresandi F.
      • Jiménez D.
      • et al.
      Home treatment in pulmonary embolism.
      In these 2 studies, the incidence of recurrent VTE, major hemorrhage, and all-cause mortality was approximately 1%, 2%, and 2%, respectively.
      • 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.
      • Otero R.
      • Uresandi F.
      • Jiménez D.
      • et al.
      Home treatment in pulmonary embolism.
      Thus, an outpatient treatment strategy for newly diagnosed PE can be deemed safe and effective if the subsequent incidence of important adverse outcomes does not exceed those experienced by patients receiving traditional hospitalization followed by outpatient care.
      Two Class II studies
      • 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.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      on behalf of the Hestia Study Investigators
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia study.
      and 7 Class III studies
      • den Exter P.L.
      • Zondag W.
      • Klok F.A.
      • et al.
      for the Vesta Study Investigators
      Efficacy and safety of outpatient treatment based on the Hestia clinical decision rule with or without N-terminal pro-brain natriuretic peptide testing in patients with acute pulmonary embolism: a randomized clinical trial.
      • Davies C.W.
      • Wimperis J.
      • Green E.S.
      • et al.
      Early discharge of patients with pulmonary embolism: a two-phase observational study.
      • Zondag W.
      • den Exter P.L.
      • Crobach M.J.
      • et al.
      on behalf of the Hestia Study Investigators
      Comparison of two methods for selection of out of hospital treatment in patients with acute pulmonary embolism.
      • Piran S.
      • Le Gal G.
      • Wells P.S.
      • et al.
      Outpatient treatment of symptomatic pulmonary embolism: a systematic review and meta-analysis.
      • Zondag W.
      • Kooiman J.
      • Klok F.A.
      • et al.
      Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta-analysis.
      • Vinson D.R.
      • Zehtabchi S.
      • Yealy D.M.
      Can selected patients with newly diagnosed pulmonary embolism be safely treated without hospitalization? a systematic review.
      • Zondag W.
      • Vingerhoets L.M.
      • Durian M.F.
      • et al.
      on behalf of the Hestia Study Investigators
      Hestia criteria can safely select patients with pulmonary embolism for outpatient treatment irrespective of right ventricular function.
      addressed this critical question, 3 of which were deemed directly applicable.
      • den Exter P.L.
      • Zondag W.
      • Klok F.A.
      • et al.
      for the Vesta Study Investigators
      Efficacy and safety of outpatient treatment based on the Hestia clinical decision rule with or without N-terminal pro-brain natriuretic peptide testing in patients with acute pulmonary embolism: a randomized clinical 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.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      on behalf of the Hestia Study Investigators
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia study.
      In each of these studies, the rates of important short-term adverse outcomes (eg, recurrent VTE, major hemorrhage, mortality) did not exceed that expected of admitted patients receiving traditional care.
      First, a Class II 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.
      prospectively randomized 344 consecutive, low-risk patients by the PESI score to either early discharge from the hospital within 24 hours (N=172) or admission to the hospital for traditional care (N=172). Both treatment arms received anticoagulation with subcutaneous LMWH for no more than 5 days followed by a VKA (ie, warfarin). Although the incidence of recurrent VTE, major hemorrhage, and all-cause mortality was similar in both treatment arms (Table 3), this open-label study had limitations.
      • 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.
      First, 126 eligible patients were not enrolled for a variety of reasons (eg, declined to participate [N=99], physician was against study participation [N=17], not randomized [N=9]); if these patients had more severe disease, not including these subjects may have resulted in an underestimation of the incidence of adverse outcomes. Next, early-discharge patients spent up to 24 hours in a health care setting, which is significantly longer than the typical ED length of stay, thus limiting the direct applicability to the critical question. Finally, the study added additional exclusion criteria during patient enrollment that were not a part of the original PESI score (eg, requiring narcotics for pain, active bleeding, risk of bleeding, renal failure, extreme obesity, heparin allergy, currently taking anticoagulation, pregnancy, barriers to adherence of the treatment protocol). Therefore, when the application of these results is considered, these additional exclusion criteria should be considered, along with the PESI score, when one seeks to identify low-risk patients for adverse outcomes.
      Table 3Rates of Adverse Outcomes in Patients with PE who were treated as outpatients.
      StudyFollow-up (Days)Outcomes
      Recurrent VTE, % (UCL)Major Hemorrhage,

      % (UCL)
      Mortality,

      % (UCL)
      Unique Composite Outcome,
      Composite outcome included recurrent VTE, bleeding-related mortality, or need for cardiopulmonary resuscitation, ICU-level care, thrombolytic therapy, or embolectomy.


      % (UCL)
      Traditional inpatient care
      • 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.
      • Otero R.
      • Uresandi F.
      • Jiménez D.
      • et al.
      Home treatment in pulmonary embolism.
      1.0 (3.3)2.0 (5.0)2.0 (11)
      Outpatient care
       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.
      Original data.
      140 (1.7)1.2 (3.6)0 (1.7)
      900.6 (2.7)1.8 (4.5)0.6 (2.1)
       Zondag et al
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      on behalf of the Hestia Study Investigators
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia study.
      Original data.
      70 (1.2)0.3 (1.9)0 (1.2)
      90
       den Exter et al
      • den Exter P.L.
      • Zondag W.
      • Klok F.A.
      • et al.
      for the Vesta Study Investigators
      Efficacy and safety of outpatient treatment based on the Hestia clinical decision rule with or without N-terminal pro-brain natriuretic peptide testing in patients with acute pulmonary embolism: a randomized clinical trial.
      Original data.
      100.3 (1.0)
      301.1 (3.2)
      901.1 (3.2)1.1 (3.2)1.1 (3.2)
       Zondag et al
      • Zondag W.
      • Kooiman J.
      • Klok F.A.
      • et al.
      Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta-analysis.
      Meta-analysis.
      1.5 (3.0)0.8 (1.4)1.6 (2.8)
      UCL, upper confidence limit.
      Composite outcome included recurrent VTE, bleeding-related mortality, or need for cardiopulmonary resuscitation, ICU-level care, thrombolytic therapy, or embolectomy.
      Original data.
      Meta-analysis.
      In another Class II study, Zondag et al
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      on behalf of the Hestia Study Investigators
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia study.
      prospectively investigated the outcomes of 297 patients with acute PE who were determined to be at low risk by the Hestia criteria. All patients were discharged from the hospital within 24 hours of their presentation, and all were treated with subcutaneous LMWH followed by a VKA. The authors reported the incidence of recurrent VTE, major hemorrhage, and mortality at both 7 days and 90 days. Although deaths did occur in the study, the authors pointed out that no patient was adjudicated as having died from recurrent VTE. The incidence of adverse outcomes in this study was similar to that previously reported among patients receiving traditional care in the hospital (Table 3). Limitations of this study include that some of the patients came from outside the ED, 6.1% of patients received LMWH only as their anticoagulation, and 26 eligible patients (7.7%) refused to participate in the study. Zondag et al
      • Zondag W.
      • den Exter P.L.
      • Crobach M.J.
      • et al.
      on behalf of the Hestia Study Investigators
      Comparison of two methods for selection of out of hospital treatment in patients with acute pulmonary embolism.
      went on to perform a Class III post hoc analysis of their original data, comparing the performance of the Hestia and sPESI low-risk rules. The authors found that the sPESI performed as well as the HESTIA criteria in identifying acute PE patients who were low risk for adverse outcomes.
      • Zondag W.
      • den Exter P.L.
      • Crobach M.J.
      • et al.
      on behalf of the Hestia Study Investigators
      Comparison of two methods for selection of out of hospital treatment in patients with acute pulmonary embolism.
      A Class III study by den Exter et al
      • den Exter P.L.
      • Zondag W.
      • Klok F.A.
      • et al.
      for the Vesta Study Investigators
      Efficacy and safety of outpatient treatment based on the Hestia clinical decision rule with or without N-terminal pro-brain natriuretic peptide testing in patients with acute pulmonary embolism: a randomized clinical trial.
      reported data from a prospective trial that followed 275 patients with acute PE who were determined to be at low risk by the Hestia criteria. All patients were treated with an LMWH followed by a VKA and discharged from the hospital within 24 hours of presentation. The 90-day incidence of recurrent VTE, major bleeding, and mortality was determined to be similar to that experienced by patients receiving traditional care in the hospital (Table 3). This study was limited by the fact that it was not clear whether the study enrolled consecutive patients or what proportion of patients were from the ED (if any). Additionally, 11 patients were excluded by their physician for a perceived “large clot burden” despite being deemed to be at low risk by the Hestia criteria.
      The findings of these 3 studies are corroborated by 3 Class III meta-analyses.
      • Piran S.
      • Le Gal G.
      • Wells P.S.
      • et al.
      Outpatient treatment of symptomatic pulmonary embolism: a systematic review and meta-analysis.
      • Zondag W.
      • Kooiman J.
      • Klok F.A.
      • et al.
      Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta-analysis.
      • Vinson D.R.
      • Zehtabchi S.
      • Yealy D.M.
      Can selected patients with newly diagnosed pulmonary embolism be safely treated without hospitalization? a systematic review.
      The more notable of these, by Zondag et al,
      • Zondag W.
      • Kooiman J.
      • Klok F.A.
      • et al.
      Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta-analysis.
      included 8 retrospective studies of various quality and found similar rates of adverse outcome, which included rates of recurrent VTE, major hemorrhage, and mortality of 1.5%, 0.8%, and 1.6%, respectively.
      Table 3 shows the summary outcomes data from these studies compared with traditional care.
      • den Exter P.L.
      • Zondag W.
      • Klok F.A.
      • et al.
      for the Vesta Study Investigators
      Efficacy and safety of outpatient treatment based on the Hestia clinical decision rule with or without N-terminal pro-brain natriuretic peptide testing in patients with acute pulmonary embolism: a randomized clinical 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.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      on behalf of the Hestia Study Investigators
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia study.
      • Zondag W.
      • Kooiman J.
      • Klok F.A.
      • et al.
      Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta-analysis.
      This, combined with the fact that nearly 50% of patients who receive a diagnosis of acute PE meet low-risk criteria, implies that approximately half of patients with newly diagnosed PE may be eligible for discharge directly home from the ED.
      • den Exter P.L.
      • Zondag W.
      • Klok F.A.
      • et al.
      for the Vesta Study Investigators
      Efficacy and safety of outpatient treatment based on the Hestia clinical decision rule with or without N-terminal pro-brain natriuretic peptide testing in patients with acute pulmonary embolism: a randomized clinical 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.
      • Zondag W.
      • Mos I.C.
      • Creemers-Schild D.
      • et al.
      on behalf of the Hestia Study Investigators
      Outpatient treatment in patients with acute pulmonary embolism: the Hestia study.
      • Zondag W.
      • Kooiman J.
      • Klok F.A.
      • et al.
      Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta-analysis.
      Currently, the additional discriminatory value of adding right ventricular dysfunction on imaging to decisionmaking in regard to low risk is controversial. Some guidelines have recommended that screening for right ventricular dysfunction on imaging be incorporated into the determination of low-risk PE despite that right ventricular dysfunction is not included as a predictive variable in the PESI, sPESI, or Hestia scores.
      • Konstantinides S.V.
      • Torbicki A.
      • Agnelli G.
      • et al.
      Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)
      2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism.
      On the other hand, Zondag et al
      • Zondag W.
      • Vingerhoets L.M.
      • Durian M.F.
      • et al.
      on behalf of the Hestia Study Investigators
      Hestia criteria can safely select patients with pulmonary embolism for outpatient treatment irrespective of right ventricular function.
      and Barrios et al
      • Barrios D.
      • Morillo R.
      • Lobo J.L.
      • et al.
      for the PROTECT investigators
      Assessment of right ventricular function in acute pulmonary embolism.
      found that screening patients for right ventricular dysfunction did not significantly improve the identification of low-risk patients with PE over the Hestia and sPESI rules, respectively; and in the case of the Hestia rule, it would have led to one-third of the truly low-risk patients who proved to have good outcomes being falsely classified as having nonlow risk.
      In summary, although existing literature supports early discharge of patients with newly diagnosed PE who are deemed to be at low risk for adverse outcomes, the current evidence supported only a Level C recommendation. To make a recommendation with a high degree of clinical certainty, studies that enroll consecutive ED patients with symptomatic PE who are discharged within a reasonable timeframe (ie, a typical ED length of stay) are needed. Also, the studies that contributed to the final recommendation of this critical question only treated patients with a LMWH followed by a VKA. Although NOACs are an approved therapy for the treatment of VTE, there are limited data assessing the safety of early discharge of patients with PE who are receiving a NOAC. Nonetheless, no current data suggests any reason why a NOAC would be inferior as a treatment regimen for this group of patients.

       Future Research

      To achieve a higher-level recommendation, future high-quality studies need to focus on the identification of those low-risk patients with acute PE who are safe for discharge from the ED, including those identified as having concurrent DVT who may be at greater risk for subsequent embolization and adverse outcome.
      • Jiménez D.
      • Aujesky D.
      • Diaz G.
      • et al.
      RIETE Investigators
      Prognostic significance of deep vein thrombosis in patients presenting with acute symptomatic pulmonary embolism.
      • Becattini C.
      • Cohen A.T.
      • Agnelli G.
      • et al.
      Risk stratification of patients with acute symptomatic pulmonary embolism based on presence or absence of lower extremity DVT. Systematic review and meta-analysis.
      Comparative effectiveness studies are also needed to determine the balance of risks and benefits for outpatient treatment of VTE with the various NOACs.
      • 5.
        In adult patients diagnosed with acute lower-extremity DVT who are discharged from the ED, is treatment with a NOAC safe and effective compared with treatment with LMWH and VKA?

       Patient Management Recommendations

       Level A recommendations

      None specified.

       Level B recommendations

      In selected patients diagnosed with acute DVT, a NOAC may be used as a safe and effective treatment alternative to LMWH/VKA.

       Level C recommendations

      Selected patients with acute DVT may be safely treated with a NOAC and directly discharged from the ED.
      Potential Benefit of Implementing the Recommendations:
      • Reduced inpatient treatment-related complications (eg, hospital-acquired infections)
      • Reduced cost compared with inpatient care or medication monitoring of VKAs
      • Reduced hospital inpatient crowding
      • Reduced time associated with treatment follow-up
      • Better use of health care resources
      • Improved patient satisfaction as a result of more efficient patient care and the ability to be treated at home
      • Improved safety profile of NOACs with reduced major or clinically relevant nonmajor bleeding compared with standard therapy
      Potential Harm of Implementing the Recommendations:
      • Increased pharmacy expense for NOAC medications
      • Lack of safe and effective reversal agents for NOACs for patients presenting with severe bleeding
      • Increased patient and provider anxiety with outpatient management of a potentially serious disease process
      • Delay in evaluation and management of changes in clinical condition, resulting from the need to return to the ED or a health care setting for evaluation and management
      Key words/phrases for literature searches: venous thrombosis, venous thromboembolism, DVT, deep venous thrombosis, thromboembolism, leg thrombosis, lower extremity thrombosis, factor Xa inhibitors, NOAC, novel oral anticoagulant, antithrombins, DOAC, rivaroxaban, apixaban, edoxaban, dabigatran, pyridones, pyrazoles, pyridines, non–vitamin K antagonist, heparin, warfarin, anticoagulants, oral administration, recurrence, risk factors, treatment outcome, patient discharge, hospital emergency or emergency room, or emergency department, or outpatient, or ambulatory care, or home care, and variations and combinations of the key words/phrases. Searches included January 1, 2006, to search dates of April 22, 2016, and May 2, 2016.
      Study Selection: Two hundred fifty-nine articles were identified in this search. Forty-five relevant articles were selected from the search results for further methodological review and grading. Three Class II and 8 Class III articles were included for this critical question.
      Traditional therapy for patients with acute lower extremity DVT is subcutaneous LMWH with simultaneous bridging administration of an oral VKA until the patient achieves a therapeutic level of anticoagulation. It has been shown to be safe and effective as an outpatient treatment regimen.
      • Kurtoglu M.
      • Koksoy C.
      • Hasan E.
      • et al.
      Long-term efficacy and safety of once-daily enoxaparin plus warfarin for the outpatient ambulatory treatment of lower-limb deep vein thrombosis in the TROMBOTEK trial.
      • Lozano F.
      • Trujillo-Santos J.
      • Barrón M.
      • et al.
      Home versus in-hospital treatment of outpatients with acute deep venous thrombosis of the lower limbs.
      • Othieno R.
      • Abu Affan M.
      • Okpo E.
      Home versus in-patient treatment for deep vein thrombosis.
      This initiation of LMWH/VKA requires extensive resources and potential hospitalization to achieve essential patient goals, including ensuring appropriate patient education, patient access to medications for home administration, and patient follow-up for laboratory monitoring of anticoagulation. If shown to be safe and effective, the administration of NOACs with subsequent direct discharge from the ED could markedly simplify the initiation and monitoring requirements for patients with newly diagnosed acute DVT.
      • Ahrens I.
      • Lip G.Y.
      • Peter K.
      New oral anticoagulant drugs in cardiovascular disease.
      Furthermore, studies have shown reduced health care costs when a NOAC is used over traditional LMWH/VKA therapy in properly chosen patients.
      • Kahler Z.P.
      • Beam D.M.
      • Kline J.A.
      Cost of treating venous thromboembolism with heparin and warfarin versus home treatment with rivaroxaban.
      • Lefebvre P.
      • Coleman C.I.
      • Bookhart B.K.
      • et al.
      Cost-effectiveness of rivaroxaban compared with enoxaparin plus a vitamin K antagonist for the treatment of venous thromboembolism.
      • Merli G.J.
      • Hollander J.E.
      • Lefebvre P.
      • et al.
      Costs of hospital visits among patients with deep vein thrombosis treated with rivaroxaban and LMWH/warfarin.
      A list of currently approved NOACs and dosing regimens is shown in Table 4. For both LMWHs and NOACs, physicians must pay attention to body mass index and renal function before initiating anticoagulation treatment.
      Table 4Comparison of NOACs for treatment of VTE.
      NOACClassTreatment Regimen for VTEPretreatment Before Initiation of Further TreatmentNotes
      Dabigatran

      (Pradaxa)
      Direct thrombin inhibitor150 mg BIDParenteral anticoagulation×5-10 daysDialyzable; reversal agent idarucizumab
      Edoxaban

      (Savaysa)
      Factor Xa inhibitor60 mg QDParenteral anticoagulation×5-10 daysLower dose of 30 mg QD for patients ≤60 kg or CrCl 15-50 mL/min
      Rivaroxaban

      (Xarelto)
      Factor Xa inhibitorInitial: 15 mg BID×21 days

      Then: 20 mg QD
      NoneTake with food
      Apixaban

      (Eliquis)
      Factor Xa inhibitorInitial: 10 mg BID×7 days

      Then: 5 mg BID
      None
      BID, two times a day; CrCl, creatinine clearance; kg, kilogram; mg, milligram; min, minute; mL, milliliter; QD, once a day.
      For this critical question, 3 Class II studies
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      for the AMPLIFY investigators
      Oral apixaban for the treatment of acute venous thromboembolism.
      • Büller H.R.
      • Décousus H.
      • Grosso M.A.
      • et al.
      the Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      and 8 Class III studies
      • Beam D.M.
      • Kahler Z.P.
      • Kline J.A.
      Immediate discharge and home treatment with rivaroxaban of low-risk venous thromboembolism diagnosed in two US emergency departments: a one-year preplanned analysis.
      • Buller H.R.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      on behalf of the EINSTEIN-DVT Dose-Ranging Study Investigators
      A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the EINSTEIN-DVT Dose-Ranging Study.
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      for the RE-COVER Study Group
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      • Prandoni P.
      • Prins M.H.
      • Cohen A.T.
      • et al.
      Use of prestudy heparin did not influence the efficacy and safety of rivaroxaban in patients treated for symptomatic venous thromboembolism in the EINSTEIN DVT and EINSTEIN PE studies.
      • Robertson L.
      • Kesteven P.
      • McCaslin J.E.
      Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.
      • Cohen A.T.
      • Hamilton M.
      • Mitchell S.A.
      • et al.
      Comparison of the novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in the initial and long-term treatment and prevention of venous thromboembolism: systematic review and network meta-analysis.
      • Kang N.
      • Sobieraj D.M.
      Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism.
      • Di Minno M.N.
      • Lupoli R.
      • Di Minno A.
      • et al.
      Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: a meta-analysis of randomized controlled trials.
      were identified comparing the efficacy and safety of NOACs with standard therapy in the treatment of acute VTE. All 3 of the Class II studies
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      for the AMPLIFY investigators
      Oral apixaban for the treatment of acute venous thromboembolism.
      • Büller H.R.
      • Décousus H.
      • Grosso M.A.
      • et al.
      the Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      and 3 of the Class III studies
      • Beam D.M.
      • Kahler Z.P.
      • Kline J.A.
      Immediate discharge and home treatment with rivaroxaban of low-risk venous thromboembolism diagnosed in two US emergency departments: a one-year preplanned analysis.
      • Buller H.R.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      on behalf of the EINSTEIN-DVT Dose-Ranging Study Investigators
      A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the EINSTEIN-DVT Dose-Ranging Study.
      • Robertson L.
      • Kesteven P.
      • McCaslin J.E.
      Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.
      specifically examined outcomes in patients receiving a diagnosis of isolated DVT, whereas the remaining 5 Class III studies
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      for the RE-COVER Study Group
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      • Prandoni P.
      • Prins M.H.
      • Cohen A.T.
      • et al.
      Use of prestudy heparin did not influence the efficacy and safety of rivaroxaban in patients treated for symptomatic venous thromboembolism in the EINSTEIN DVT and EINSTEIN PE studies.
      • Cohen A.T.
      • Hamilton M.
      • Mitchell S.A.
      • et al.
      Comparison of the novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in the initial and long-term treatment and prevention of venous thromboembolism: systematic review and network meta-analysis.
      • Kang N.
      • Sobieraj D.M.
      Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism.
      • Di Minno M.N.
      • Lupoli R.
      • Di Minno A.
      • et al.
      Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: a meta-analysis of randomized controlled trials.
      examined cohorts that included patients with DVT and PE.
      Of the 11 Class II and Class III studies, only 1 directly addressed safety and efficacy outcomes in patients who began receiving a NOAC and were directly discharged from the ED.
      • Beam D.M.
      • Kahler Z.P.
      • Kline J.A.
      Immediate discharge and home treatment with rivaroxaban of low-risk venous thromboembolism diagnosed in two US emergency departments: a one-year preplanned analysis.
      This multicenter Class III study examined the safety and efficacy of a protocol for the outpatient treatment of patients with newly diagnosed VTE. Per protocol, patients at low risk for adverse outcomes based on a modified version of the Hestia criteria were treated with oral rivaroxaban and discharged from the ED with arranged outpatient follow-up. Of the 271 eligible VTE patients, 39% were deemed to be at low risk and treated per study protocol, and were discharged directly from the ED. These patients represented 51% of all new DVT diagnoses and 27% of all new PE diagnoses during the study period. No patient discharged on oral rivaroxaban had recurrent VTE or a clinically relevant bleeding event while receiving therapy (95% CI 0% to 3.4%). Three patients had recurrent DVT after cessation of therapy, and 2 patients experienced death unrelated to VTE or rivaroxaban. The authors concluded that ED discharge on oral rivaroxaban for properly selected patients with acute DVT diagnosis is safe and effective. The major limitation of this study was that subjects were not randomized, potentially leading to a biased sample based on clinician judgment to enroll patients in the study versus admit them to the hospital.
      • Beam D.M.
      • Kahler Z.P.
      • Kline J.A.
      Immediate discharge and home treatment with rivaroxaban of low-risk venous thromboembolism diagnosed in two US emergency departments: a one-year preplanned analysis.
      Of the remaining 10 studies, 3 Class II studies
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      for the AMPLIFY investigators
      Oral apixaban for the treatment of acute venous thromboembolism.
      • Büller H.R.
      • Décousus H.
      • Grosso M.A.
      • et al.
      the Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      depicted the efficacy and safety of NOACs versus LMWH/VKA in patients with a diagnosis of isolated DVT or in patients with a diagnosis of VTE (ie, DVT or PE) but with clinical outcome data reported for index DVT. The Class II DVT study by the EINSTEIN Investigators
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      was the first to focus specifically on the treatment of acute DVT with a NOAC. In this open-label, noninferiority study, patients receiving a diagnosis of acute DVT were randomized to treatment with either oral rivaroxaban alone (N=1,731) or traditional therapy (n=1,718). The rivaroxaban arm had noninferior efficacy compared with standard therapy, as measured by recurrent VTE (2.1% versus 3.0%; hazard ratio 0.7; 95% CI 0.4 to 1.0) and major bleeding during treatment (8.1% versus 8.1%; hazard ratio 1; 95% CI 0.8 to 1.2).
      The other 2 Class II studies
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      for the AMPLIFY investigators
      Oral apixaban for the treatment of acute venous thromboembolism.
      • Büller H.R.
      • Décousus H.
      • Grosso M.A.
      • et al.
      the Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      considered patients with isolated DVT, or PE with or without DVT, and analyzed outcomes stratified by the index event. The multicenter, double-blinded Apixaban for the initial management of PE and DVT as first-line therapy (AMPLIFY) study
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      for the AMPLIFY investigators
      Oral apixaban for the treatment of acute venous thromboembolism.
      randomized 5,395 patients with newly diagnosed VTE to either oral apixaban or standard therapy. Sixty-five percent of enrolled patients had an isolated acute DVT, and of these, the primary efficacy outcome of recurrent VTE occurred in 2.3% of those in the apixaban group versus 2.7% receiving conventional therapy (risk difference –0.5%; 95% CI –1.5% to 0.6%). The primary safety outcome of major bleeding occurred in 0.6% of patients in the apixaban arm versus 1.8% in the conventional arm (risk difference –1.1%; 95% CI –1.7 to –0.6), thus favoring the use of apixaban in terms of safety. The multicenter, double-blinded Hokusai-VTE study
      • Büller H.R.
      • Décousus H.
      • Grosso M.A.
      • et al.
      the Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      randomized patients with acute VTE to either edoxaban or a VKA; all patients received at least 5 days of parenteral anticoagulation. Of the 8,292 patients enrolled, 59% presented with isolated DVT as the index event. Among this subgroup, a recurrent VTE during the study period occurred in 3.4% (83/2,468) of patients receiving edoxaban versus 3.3% (81/2,453) of patients receiving warfarin (hazard ratio 1; 95% CI 0.8 to 1.4). For all enrolled patients (eg, PE, DVT), the primary safety outcome of major or clinically relevant nonmajor bleeding was less in those treated with edoxaban versus standard therapy, occurring in 8.5% of patients treated with edoxaban versus 10.3% treated with VKA (hazard ratio 0.8; 95% CI 0.7 to 0.9). These 2 studies showed similar efficacy, but improved safety for treatments with a NOAC with or without LWMH versus traditional therapy in patients with acute DVT.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      for the AMPLIFY investigators
      Oral apixaban for the treatment of acute venous thromboembolism.
      • Büller H.R.
      • Décousus H.
      • Grosso M.A.
      • et al.
      the Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      Three Class III research studies
      • Buller H.R.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      on behalf of the EINSTEIN-DVT Dose-Ranging Study Investigators
      A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the EINSTEIN-DVT Dose-Ranging Study.
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      for the RE-COVER Study Group
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      • Prandoni P.
      • Prins M.H.
      • Cohen A.T.
      • et al.
      Use of prestudy heparin did not influence the efficacy and safety of rivaroxaban in patients treated for symptomatic venous thromboembolism in the EINSTEIN DVT and EINSTEIN PE studies.
      evaluated the use of NOACs alone or in combination with LMWH for the treatment of acute VTE. A phase 2 industry-sponsored dose-ranging study evaluated once-daily rivaroxaban (20, 30, or 40 mg) versus LMWH/VKA for acute symptomatic DVT without PE.
      • Buller H.R.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      on behalf of the EINSTEIN-DVT Dose-Ranging Study Investigators
      A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the EINSTEIN-DVT Dose-Ranging Study.
      Efficacy and safety were similar among all 4 groups, justifying progression to the phase 3 EINSTEIN-DVT study described above.
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      In 2009, Schulman et al
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      for the RE-COVER Study Group
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      (the RE-COVER trial) compared dabigatran versus warfarin in the treatment of acute VTE. This Class III study
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      for the RE-COVER Study Group
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      was a double-blind noninferiority trial randomizing patients with newly diagnosed PE or DVT to treatment with dabigatran or warfarin for 6 months. Sixty-nine percent of patients in this study had an isolated acute DVT, but outcomes were not stratified by index event. Patients in both groups received concurrent initial treatment with parenteral anticoagulation for at least 5 days. This trial found dabigatran to be noninferior to warfarin for the prevention of recurrent VTE (2.4% versus 2.1%). Rates of bleeding with dabigatran were similar to or lower than those with warfarin. The number of deaths, acute coronary syndromes, and abnormal liver function test results were also similar between the 2 groups.
      The effect of prestudy heparin on the efficacy and safety of rivaroxaban relative to standard therapy and the incidence of bleeding compared with that of patients who did not receive prestudy heparin was evaluated in a Class III study by Prandoni et al.
      • Prandoni P.
      • Prins M.H.
      • Cohen A.T.
      • et al.
      Use of prestudy heparin did not influence the efficacy and safety of rivaroxaban in patients treated for symptomatic venous thromboembolism in the EINSTEIN DVT and EINSTEIN PE studies.
      This retrospective, post hoc analysis of the EINSTEIN-DVT
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      and EINSTEIN-PE
      • Büller H.R.
      • Prins M.H.
      • Lensing A.W.
      • et al.
      for the EINSTEIN-PE Investigators
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      studies found that the majority of patients (84%) enrolled in the EINSTEIN-DVT and PE studies received prestudy heparin but with most (70%) receiving prestudy heparin for 1 day or less. There was no difference observed in the incidence of recurrent VTE or bleeding between the groups.
      Four Class III meta-analyses
      • Robertson L.
      • Kesteven P.
      • McCaslin J.E.
      Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.
      • Cohen A.T.
      • Hamilton M.
      • Mitchell S.A.
      • et al.
      Comparison of the novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in the initial and long-term treatment and prevention of venous thromboembolism: systematic review and network meta-analysis.
      • Kang N.
      • Sobieraj D.M.
      Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism.
      • Di Minno M.N.
      • Lupoli R.
      • Di Minno A.
      • et al.
      Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: a meta-analysis of randomized controlled trials.
      compared the safety and efficacy of NOACs versus traditional therapy. In 2015, Robertson et al
      • Robertson L.
      • Kesteven P.
      • McCaslin J.E.
      Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.
      found NOACs with or without LMWH to be an effective and safe alternative to traditional anticoagulation treatment of acute DVT. This analysis included 11 randomized controlled trials of 27,945 patients, 5 of which are discussed above
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      for the AMPLIFY investigators
      Oral apixaban for the treatment of acute venous thromboembolism.
      • Büller H.R.
      • Décousus H.
      • Grosso M.A.
      • et al.
      the Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      • Buller H.R.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      on behalf of the EINSTEIN-DVT Dose-Ranging Study Investigators
      A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the EINSTEIN-DVT Dose-Ranging Study.
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      for the RE-COVER Study Group
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      and 6 of which are not included in this review (1 was deemed not directly relevant to the critical question,
      • Büller H.R.
      • Prins M.H.
      • Lensing A.W.
      • et al.
      for the EINSTEIN-PE Investigators
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      2 were reviewed and graded Class X,
      • Buller H.
      • Deitchman D.
      • Prins M.
      • et al.
      on behalf of the Botticelli Investigators, the Writing Committee
      Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study.
      • Schulman S.
      • Kakkar A.K.
      • Goldhaber S.Z.
      • et al.
      Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis.
      1 was abstract data only,
      • Piazza G.
      • Mani V.
      • Grosso M.
      • et al.
      Abstract 12074: a randomized, open-label, multicenter study of the efficacy and safety of edoxaban monotherapy versus low-molecular weight heparin/warfarin in patients with symptomatic deep vein thrombosis—Edoxaban Thrombus Reduction Imaging Study (eTRIS).
      1 was a proof-of-concept study,
      • Agnelli G.
      • Gallus A.
      • Goldhaber S.Z.
      • et al.
      Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in patients with acute symptomatic deep-vein thrombosis) study.
      and 1 was a study on a non–Food and Drug Administration– approved NOAC
      • Eriksson H.
      • Wåhlander K.
      • Gustafsson D.
      • et al.
      for the THRIVE Investigators
      A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I.
      ). It included separate meta-analyses assessing the effectiveness of oral direct thrombin inhibitors (ie, dabigatran) or oral factor Xa inhibitors (ie, apixaban, edoxaban, rivaroxaban).
      • Robertson L.
      • Kesteven P.
      • McCaslin J.E.
      Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.
      Meta-analysis comparing oral direct thrombin inhibitors versus traditional therapy showed no difference in the rate of recurrent VTE (odds ratio [OR] 1.09; 95% CI 0.80 to 1.49) but did show reduced bleeding rates (OR 0.68; 95% CI 0.47 to 0.98).
      • Robertson L.
      • Kesteven P.
      • McCaslin J.E.
      Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.
      Similarly, meta-analysis comparing oral factor Xa inhibitors with traditional therapy showed similar rates of recurrent VTE (OR 0.89; 95% CI 0.73 to 1.07), with reduced rates of bleeding (OR 0.57; 95% CI 0.43 to 0.76).
      • Robertson L.
      • Kesteven P.
      • McCaslin J.E.
      Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.
      Two other Class III meta-analyses were conducted to compare the safety and efficacy of NOACs in the treatment of VTE (ie, DVT or PE)
      • Cohen A.T.
      • Hamilton M.
      • Mitchell S.A.
      • et al.
      Comparison of the novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in the initial and long-term treatment and prevention of venous thromboembolism: systematic review and network meta-analysis.
      • Kang N.
      • Sobieraj D.M.
      Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism.
      ; both included 6 phase 3 randomized controlled trials
      • Bauersachs R.
      • Berkowitz S.D.
      • Brenner B.
      • et al.
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • Agnelli G.
      • Buller H.R.
      • Cohen A.
      • et al.
      for the AMPLIFY investigators
      Oral apixaban for the treatment of acute venous thromboembolism.
      • Büller H.R.
      • Décousus H.
      • Grosso M.A.
      • et al.
      the Hokusai-VTE Investigators
      Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      for the RE-COVER Study Group
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      • Büller H.R.
      • Prins M.H.
      • Lensing A.W.
      • et al.
      for the EINSTEIN-PE Investigators
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      • Schulman S.
      • Kakkar A.K.
      • Goldhaber S.Z.
      • et al.
      Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis.
      and showed that there was no significant difference between the NOACs in regard to the risk of recurrent VTE, mortality, or safety. The fourth Class III meta-analysis by Di Minno et al
      • Di Minno M.N.
      • Lupoli R.
      • Di Minno A.
      • et al.
      Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: a meta-analysis of randomized controlled trials.
      included the same 6 studies as above and showed similar safety and efficacy of treatment with NOACs versus VKA among patients of various body weights.

       Future Research

      Although evidence exists to support the use of NOACs to treat DVT, future research should focus on direct comparison of individual NOACs in relation to efficacy, bleeding risks, adverse effects, and patient preferences. Furthermore, high-quality research should focus on the efficacy and safety of NOACs for outpatient treatment of patients diagnosed with VTE and the need for LMWH as pretreatment before initiation of specific NOACs, including dabigatran and edoxaban.
      Relevant industry relationships: There were no relevant industry relationships disclosed by the subcommittee members for this topic.
      Relevant industry relationships are those relationships with companies associated with products or services that significantly impact the specific aspect of disease addressed in the critical question.

      Appendix

      Appendix ALiterature classification schema.
      Some designs (eg, surveys) will not fit this schema and should be assessed individually.
      Design/ClassTherapy
      Objective is to measure therapeutic efficacy comparing interventions.
      Diagnosis
      Objective is to determine the sensitivity and specificity of diagnostic tests.
      Prognosis
      Objective is to predict outcome, including mortality and morbidity.
      1Randomized, controlled trial or meta-analysis of randomized trialsProspective cohort using a criterion standard or meta-analysis of prospective studiesPopulation prospective cohort or meta-analysis of prospective studies
      2Nonrandomized trialRetrospective observationalRetrospective cohort

      Case control
      3Case seriesCase seriesCase series
      Some designs (eg, surveys) will not fit this schema and should be assessed individually.
      Objective is to measure therapeutic efficacy comparing interventions.
      Objective is to determine the sensitivity and specificity of diagnostic tests.
      § Objective is to predict outcome, including mortality and morbidity.
      Appendix BApproach to downgrading strength of evidence.
      DowngradingDesign/Class
      123
      NoneIIIIII
      1 levelIIIIIX
      2 levelsIIIXX
      Fatally flawedXXX
      Appendix CLikelihood ratios and number needed to treat.
      Number needed to treat (NNT): number of patients who need to be treated to achieve 1 additional good outcome; NNT=1/absolute risk reduction×100, where absolute risk reduction is the risk difference between 2 event rates (ie, experimental and control groups).
      LR (+)LR (-)
      1.01.0Does not change pretest probability
      1-50.5-1Minimally changes pretest probability
      100.1May be diagnostic if the result is concordant with pretest probability
      200.05Usually diagnostic
      1000.01Almost always diagnostic even in the setting of low or high pretest probability
      LR, likelihood ratio.
      Number needed to treat (NNT): number of patients who need to be treated to achieve 1 additional good outcome; NNT=1/absolute risk reduction×100, where absolute risk reduction is the risk difference between 2 event rates (ie, experimental and control groups).

      Evidentiary Table

      Figure thumbnail fx1
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      Figure thumbnail fx7
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      Figure thumbnail fx11
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      Figure thumbnail fx13
      Figure thumbnail fx14
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      Figure thumbnail fx16
      Figure thumbnail fx17
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      Figure thumbnail fx19
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      Figure thumbnail fx29
      Figure thumbnail fx30

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