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Antithrombotic therapy for vte disease
[ Evidence-Based Medicine ]
Antithrombotic Therapy for VTE DiseaseCHEST Guideline and Expert Panel Report
Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Joseph Ornelas, PhD; Allen Blaivas, DO, FCCP;
David Jimenez, MD, PhD, FCCP; Henri Bounameaux, MD; Menno Huisman, MD, PhD;
Christopher S. King, MD, FCCP; Timothy A. Morris, MD, FCCP; Namita Sood, MD, FCCP;
Scott M. Stevens, MD; Janine R. E. Vintch, MD, FCCP; Philip Wells, MD; Scott C. Woller, MD;
and COL Lisa Moores, MD, FCCP
BACKGROUND: We update recommendations on 12 topics that were in the 9th edition of theseguidelines, and address 3 new topics.
METHODS: We generate strong (Grade 1) and weak (Grade 2) recommendations based onhigh- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence.
RESULTS: For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran(Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) overvitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weightheparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B),dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade2C). We have not changed recommendations for who should stop anticoagulation at3 months or receive extended therapy. For VTE treated with anticoagulants, we recommendagainst an inferior vena cava filter (Grade 1B). For DVT, we suggest not using compressionstockings routinely to prevent PTS (Grade 2B). For subsegmental pulmonary embolism andno proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk ofrecurrent VTE (Grade 2C), and anticoagulation over clinical surveillance with a high risk(Grade 2C). We suggest thrombolytic therapy for pulmonary embolism with hypotension(Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C). Forrecurrent VTE on a non-LMWH anticoagulant, we suggest LMWH (Grade 2C); for recurrentVTE on LMWH, we suggest increasing the LMWH dose (Grade 2C).
CONCLUSIONS: Of 54 recommendations included in the 30 statements, 20 were strong andnone was based on high-quality evidence, highlighting the need for further research.
CHEST 2016; 149(2):315-352
KEY WORDS: antithrombotic therapy; evidence-based medicine; GRADE approach; venousthromboembolism
FOR EDITORIAL COMMENT SEE PAGE 293
ABBREVIATIONS: AT9 = 9th Edition of the Antithrombotic Guideline;
Lebanon; CHEST (Dr Ornelas), Glenview, IL; VA New Jersey Health
AT10 = 10th Edition of the Antithrombotic Guideline; CHEST =
Care System (Dr Blaivas), Newark, NJ; Hospital Ramón y Cajal and
American College of Chest Physicians; CDT = catheter-directed
Instituto Ramón y Cajal de Investigación Sanitaria, Universidad de
thrombolysis; COI = conflict of interest; CTEPH = chronic thrombo-
Alcala (Dr Jimenez), Madrid, Spain; University of Geneva (Dr Bou-
embolic pulmonary hypertension; CTPA = CT pulmonary angiogram;
nameaux), Geneva, Switzerland; Leiden University Medical Center (Dr
GOC = Guidelines Oversight Committee; INR = International
Huisman), Leiden, Netherlands; Virginia Commonwealth University
Normalized Ratio; IVC = inferior vena cava; LMWH = low-molecular-
(Dr King), Falls Church, VA; University of California (Dr Morris), San
weight heparin; NOAC = non-vitamin K oral anticoagulant; PE =
Diego, CA; The Ohio State University (D. Sood), Columbus, OH;
pulmonary embolism; PTS = postthrombotic syndrome; RCT = ran-
Intermountain Medical Center and the University of Utah (Drs Stevens
domized controlled trial; UEDVT = upper extremity deep vein
and Woller), Murray, UT; Harbor-UCLA Medical Center (Dr Vintch),
thrombosis; US = ultrasound; VKA = vitamin K antagonist
Torrance, CA; The University of Ottawa and Ottawa Hospital Research
AFFILIATIONS: From McMaster University (Drs Kearon and Akl),
Institute (Dr Wells), Ottawa, ON; Uniformed Services University of the
Hamilton, ON; American University of Beirut (Dr Akl), Beirut,
Health Sciences (Dr Moores), Bethesda, MD.
Note on Shaded Text: In this guideline, shaded text with
rivaroxaban and apixaban, and is overlapped with VKA
an asterisk (shading appears in PDF only) indicates
therapy. See text for factors that influence choice of
recommendations that are newly added or have been
changed since the publication of Antithrombotic Therapyfor VTE Disease: Antithrombotic Therapy and Prevention
*3. In patients with DVT of the leg or PE and cancer
of Thrombosis (9th edition): American College of Chest
("cancer-associated thrombosis"), as long-term (first
Physicians Evidence-Based Clinical Practice Guidelines.
3 months) anticoagulant therapy, we suggest LMWH
Recommendations that remain unchanged since that
over VKA therapy (Grade 2C), dabigatran (Grade
edition are not shaded. The order of our presentation of the
2C), rivaroxaban (Grade 2C), apixaban (Grade 2C),
non-vitamin K oral anticoagulants (dabigatran,
or edoxaban (Grade 2C).
rivaroxaban, apixaban, edoxaban) is based on thechronology of publication of the phase 3 trials in VTE
Remarks: Initial parenteral anticoagulation is given
treatment and should not be interpreted as the guideline
before dabigatran and edoxaban, is not given before
panel's order of preference for the use of these agents.
rivaroxaban and apixaban, and is overlapped with VKAtherapy. See text for factors that influence choice oftherapy.
Summary of Recommendations
Choice of Long-Term (First 3 Months) and Extended
*4. In patients with DVT of the leg or PE who receive
(No Scheduled Stop Date) Anticoagulant
extended therapy, we suggest that there is no need
1. In patients with proximal DVT or pulmonary
to change the choice of anticoagulant after the first
embolism (PE), we recommend long-term (3 months)
3 months (Grade 2C).
anticoagulant therapy over no such therapy (Grade 1B).
Remarks: It may be appropriate for the choice of
*2. In patients with DVT of the leg or PE and no
anticoagulant to change in response to changes in the
cancer, as long-term (first 3 months) anticoagulant
patient's circumstances or preferences during long-term
therapy, we suggest dabigatran, rivaroxaban, apix-
or extended phases of treatment.
aban, or edoxaban over vitamin K antagonist (VKA)therapy (all Grade 2B).
Duration of Anticoagulant Therapy
For patients with DVT of the leg or PE and no cancer
5. In patients with a proximal DVT of the leg or
who are not treated with dabigatran, rivaroxaban,
PE provoked by surgery, we recommend treatment
apixaban, or edoxaban, we suggest VKA therapy over
with anticoagulation for 3 months over (i) treatment
low-molecular weight heparin (LMWH) (Grade 2C).
of a shorter period (Grade 1B), (ii) treatment of alonger time-limited period (eg, 6, 12, or 24 months)
Remarks: Initial parenteral anticoagulation is given
(Grade 1B), or (iii) extended therapy (no scheduled
before dabigatran and edoxaban, is not given before
stop date) (Grade 1B).
6. In patients with a proximal DVT of the leg or
DISCLAIMER: American College of Chest Physician guidelines are
PE provoked by a nonsurgical transient risk factor,
intended for general information only, are not medical advice, and donot replace professional medical care and physician advice, which
we recommend treatment with anticoagulation for
always should be sought for any medical condition. The complete
3 months over (i) treatment of a shorter period
disclaimer for this guideline can be accessed at
(Grade 1B) and (ii) treatment of a longer time-limited
period (eg, 6, 12, or 24 months) (Grade 1B). We
FUNDING/SUPPORT: This guideline was supported solely by internal
suggest treatment with anticoagulation for 3 months
funds from The American College of Chest Physicians.
ENDORSEMENTS: This guideline is endorsed by the American Asso-
over extended therapy if there is a low or moderate
ciation for Clinical Chemistry, the American College of Clinical
bleeding risk (Grade 2B), and recommend treatment
Pharmacy, the International Society for Thrombosis and Haemostasis,
for 3 months over extended therapy if there is a high
and the American Society of Health-System Pharmacists.
CORRESPONDENCE TO: Elie A. Akl, MD, MPH, PhD, Department of
risk of bleeding (Grade 1B).
Internal Medicine, Faculty of Medicine, American University of Beirut,PO Box 11-0236, Riad-El-Solh Beirut 1107 2020, Lebanon; e-mail:
Remarks: In all patients who receive extended
anticoagulant therapy, the continuing use of
Copyright Ó 2016 American College of Chest Physicians. Published byElsevier Inc. All rights reserved.
treatment should be reassessed at periodic intervals
(eg, annually).
Evidence-Based Medicine
7. In patients with an isolated distal DVT of the leg
scheduled stop date) over 3 months (Grade 1B);
provoked by surgery or by a nonsurgical transient risk
(ii) moderate bleeding risk (see text), we suggest
factor, we suggest treatment with anticoagulation for
extended anticoagulant therapy over 3 months of therapy
3 months over treatment of a shorter period (Grade 2C),
(Grade 2B); or (iii) high bleeding risk (see text), we
we recommend treatment with anticoagulation for
suggest 3 months of anticoagulant therapy over
3 months over treatment of a longer time-limited
extended therapy (no scheduled stop date) (Grade 2B).
period (eg, 6, 12, or 24 months) (Grade 1B), and we
Remarks: In all patients who receive extended
recommend treatment with anticoagulation for
anticoagulant therapy, the continuing use of treatment
3 months over extended therapy (no scheduled stop
should be reassessed at periodic intervals (eg, annually).
date) (Grade 1B).
11. In patients with DVT of the leg or PE and active
Remarks: Duration of treatment of patients with isolated
cancer ("cancer-associated thrombosis") and who
distal DVT refers to patients in whom a decision has
(i) do not have a high bleeding risk, we recommend
been made to treat with anticoagulant therapy; however,
extended anticoagulant therapy (no scheduled stop
it is anticipated that not all patients who are diagnosed
date) over 3 months of therapy (Grade 1B), or (ii) have
with isolated distal DVT will be prescribed
a high bleeding risk, we suggest extended anticoagulant
therapy (no scheduled stop date) over 3 months of
8. In patients with an unprovoked DVT of the leg
therapy (Grade 2B).
(isolated distal or proximal) or PE, we recommend
Remarks: In all patients who receive extended
treatment with anticoagulation for at least 3 months
anticoagulant therapy, the continuing use of treatment
over treatment of a shorter duration (Grade 1B), and
should be reassessed at periodic intervals (eg, annually).
we recommend treatment with anticoagulation for3 months over treatment of a longer time-limitedperiod (eg, 6, 12, or 24 months) (Grade 1B).
Aspirin for Extended Treatment of VTE
Remarks: After 3 months of treatment, patients with
*12. In patients with an unprovoked proximal DVT
unprovoked DVT of the leg or PE should be evaluated
or PE who are stopping anticoagulant therapy and
for the risk-benefit ratio of extended therapy. Duration
do not have a contraindication to aspirin, we suggest
of treatment of patients with isolated distal DVT refers
aspirin over no aspirin to prevent recurrent VTE
to patients in whom a decision has been made to treat
with anticoagulant therapy; however, it is anticipated
Remarks: Because aspirin is expected to be much less
that not all patients who are diagnosed with isolated
effective at preventing recurrent VTE than
distal DVT will be prescribed anticoagulants.
anticoagulants, we do not consider aspirin a reasonable
9. In patients with a first VTE that is an unprovoked
alternative to anticoagulant therapy in patients who
proximal DVT of the leg or PE and who have a (i) low
want extended therapy. However, if a patient has
or moderate bleeding risk (see text), we suggest
decided to stop anticoagulants, prevention of recurrent
extended anticoagulant therapy (no scheduled stop
VTE is one of the benefits of aspirin that needs to be
date) over 3 months of therapy (Grade 2B), and
balanced against aspirin's risk of bleeding and
(ii) high bleeding risk (see text), we recommend
inconvenience. Use of aspirin should also be reevaluated
3 months of anticoagulant therapy over extended
when patients stop anticoagulant therapy because
therapy (no scheduled stop date) (Grade 1B).
aspirin may have been stopped when anticoagulantswere started.
Remarks: Patient sex and D-dimer level measured amonth after stopping anticoagulant therapy mayinfluence the decision to stop or extend anticoagulant
Whether and How to Anticoagulate Isolated
therapy (see text). In all patients who receive extended
anticoagulant therapy, the continuing use of treatment
13. In patients with acute isolated distal DVT of the
should be reassessed at periodic intervals (eg, annually).
leg and (i) without severe symptoms or risk factors for
10. In patients with a second unprovoked VTE
extension (see text), we suggest serial imaging of the
and who have a (i) low bleeding risk (see text), we
deep veins for 2 weeks over anticoagulation (Grade 2C)
recommend extended anticoagulant therapy (no
or (ii) with severe symptoms or risk factors for
extension (see text), we suggest anticoagulation over
Whether to Anticoagulate Subsegmental PE
serial imaging of the deep veins (Grade 2C).
*19. In patients with subsegmental PE (no involve-
Remarks: Patients at high risk for bleeding are more
ment of more proximal pulmonary arteries) and
likely to benefit from serial imaging. Patients who place
no proximal DVT in the legs who have a (i) low
a high value on avoiding the inconvenience of repeat
risk for recurrent VTE (see text), we suggest clinical
imaging and a low value on the inconvenience of
surveillance over anticoagulation (Grade 2C) or
treatment and on the potential for bleeding are likely
(ii) high risk for recurrent VTE (see text), we
to choose initial anticoagulation over serial imaging.
suggest anticoagulation over clinical surveillance(Grade 2C).
14. In patients with acute isolated distal DVT ofthe leg who are managed with anticoagulation, we
Remarks: Ultrasound (US) imaging of the deep veins
recommend using the same anticoagulation as for
of both legs should be done to exclude proximal DVT.
patients with acute proximal DVT (Grade 1B).
Clinical surveillance can be supplemented by serial US
15. In patients with acute isolated distal DVT of
imaging of the proximal deep veins of both legs to
the leg who are managed with serial imaging, we
detect evolving DVT (see text). Patients and physicians
(i) recommend no anticoagulation if the thrombus
are more likely to opt for clinical surveillance over
does not extend (Grade 1B), (ii) suggest anticoagulation
anticoagulation if there is good cardiopulmonary reserve
if the thrombus extends but remains confined to
or a high risk of bleeding.
the distal veins (Grade 2C), and (iii) recommendanticoagulation if the thrombus extends into the
Treatment of Acute PE Out of the Hospital
proximal veins (Grade 1B).
*20. In patients with low-risk PE and whose home
Catheter-Directed Thrombolysis for Acute
circumstances are adequate, we suggest treatmentat home or early discharge over standard
discharge (eg, after the first 5 days of treatment)
16. In patients with acute proximal DVT of the leg,
we suggest anticoagulant therapy alone over CDT(Grade 2C).
Remarks: Patients who are most likely to benefit from
Systemic Thrombolytic Therapy for PE
CDT (see text), who attach a high value to prevention of
21. In patients with acute PE associated with
postthrombotic syndrome (PTS), and a lower value to the
hypotension (eg, systolic BP <90 mm Hg) who do not
initial complexity, cost, and risk of bleeding with CDT,
have a high bleeding risk, we suggest systemically
are likely to choose CDT over anticoagulation alone.
administered thrombolytic therapy over no suchtherapy (Grade 2B).
Role of Inferior Vena Cava Filter in Additionto Anticoagulation for Acute DVT or PE
*22. In most patients with acute PE not associatedwith hypotension, we recommend against
17. In patients with acute DVT or PE who are treated
systemically administered thrombolytic therapy
with anticoagulants, we recommend against the use of
an inferior vena cava (IVC) filter (Grade 1B).
*23. In selected patients with acute PE who deteri-
Compression Stocking to Prevent PTS
orate after starting anticoagulant therapy but have
*18. In patients with acute DVT of the leg, we sug-
yet to develop hypotension and who have a low
gest not using compression stockings routinely to
bleeding risk, we suggest systemically administered
prevent PTS (Grade 2B).
thrombolytic therapy over no such therapy(Grade 2C).
Remarks: This recommendation focuses on preventionof the chronic complication of PTS and not on the
Remarks: Patients with PE and without hypotension
treatment of symptoms. For patients with acute or
who have severe symptoms or marked cardiopulmonary
chronic symptoms, a trial of graduated compression
impairment should be monitored closely for
stockings is often justified.
deterioration. Development of hypotension suggests that
Evidence-Based Medicine
thrombolytic therapy has become indicated.
mechanical and pharmacological interventions designed
Cardiopulmonary deterioration (eg, symptoms, vital
to lower pulmonary arterial pressure.
signs, tissue perfusion, gas exchange, cardiacbiomarkers) that has not progressed to hypotension mayalso alter the risk-benefit assessment in favor of
Thrombolytic Therapy in Patients With Upper
thrombolytic therapy in patients initially treated with
27. In patients with acute upper extremity DVT(UEDVT) that involves the axillary or more proximal
Catheter-Based Thrombus Removal for the
veins, we suggest anticoagulant therapy alone over
Initial Treatment of PE
thrombolysis (Grade 2C).
*24. In patients with acute PE who are treated with a
Remarks: Patients who (i) are most likely to benefit
thrombolytic agent, we suggest systemic thrombo-
from thrombolysis (see text); (ii) have access to CDT;
lytic therapy using a peripheral vein over CDT
(iii) attach a high value to prevention of PTS; and
(iv) attach a lower value to the initial complexity, cost, andrisk of bleeding with thrombolytic therapy are likely to
Remarks: Patients who have a higher risk of bleeding
choose thrombolytic therapy over anticoagulation alone.
with systemic thrombolytic therapy and who have accessto the expertise and resources required to do CDT
28. In patients with UEDVT who undergo
are likely to choose CDT over systemic thrombolytic
thrombolysis, we recommend the same intensity
and duration of anticoagulant therapy as in patientswith UEDVT who do not undergo thrombolysis
*25. In patients with acute PE associated with
hypotension and who have (i) a high bleeding risk,(ii) failed systemic thrombolysis, or (iii) shock that islikely to cause death before systemic thrombolysis can
Management of Recurrent VTE on
take effect (eg, within hours), if appropriate expertise
Anticoagulant Therapy
and resources are available, we suggest catheter-assisted thrombus removal over no such intervention
*29. In patients who have recurrent VTE on VKA
therapy (in the therapeutic range) or on dabigatran,rivaroxaban, apixaban, or edoxaban (and are
Remarks: Catheter-assisted thrombus removal refers
believed to be compliant), we suggest switching
to mechanical interventions, with or without catheter
to treatment with LMWH at least temporarily
Pulmonary Thromboendarterectomy for the
Remarks: Recurrent VTE while on therapeutic-dose
Treatment of Chronic Thromboembolic
anticoagulant therapy is unusual and should prompt the
Pulmonary Hypertension
following assessments: (1) reevaluation of whether theretruly was a recurrent VTE; (2) evaluation of compliance
*26. In selected patients with chronic thromboem-
with anticoagulant therapy; and (3) consideration of
bolic pulmonary hypertension (CTEPH) who are
an underlying malignancy. A temporary switch to
identified by an experienced thromboendarter-
LMWH will usually be for at least 1 month.
ectomy team, we suggest pulmonary thromboen-darterectomy over no pulmonary
*30. In patients who have recurrent VTE on long-
thromboendarterectomy (Grade 2C).
term LMWH (and are believed to be compliant),we suggest increasing the dose of LMWH by about
Remarks: Patients with CTEPH should be evaluated by a
one-quarter to one-third (Grade 2C).
team with expertise in treatment of pulmonaryhypertension. Pulmonary thromboendarterectomy is
Remarks: Recurrent VTE while on therapeutic-dose
often lifesaving and life-transforming. Patients with
anticoagulant therapy is unusual and should prompt the
CTEPH who are not candidates for pulmonary
following assessments: (1) reevaluation of whether there
thromboendarterectomy may benefit from other
truly was a recurrent VTE; (2) evaluation of compliance
with anticoagulant therapy; and (3) consideration of an
particularly in relation the use of non-vitamin K
oral anticoagulants (NOACs). Moreover, several VTEtreatment questions that were not addressed in the last
CHEST has been developing and publishing guidelines
edition have been highlighted. This article focuses on
for the treatment of DVT and PE, collectively referred to
new developments and ongoing controversies in the
as VTE, for more than 30 years. CHEST published the
treatment of VTE, updating recommendations for
last (9th) edition of these guidelines in February 2012
12 topics that were included in AT9, and providing
(AT9).Since then, a substantial amount of new evidence
recommendations for 3 new topics. The target users of
relating to the treatment of VTE has been published,
this guideline are clinicians.
Study Selection, Data Abstraction, and Data Analysis
Composition and Selection of Topic Panel Members
The criteria for selecting the evidence were based on the Population,Intervention, Comparator, Outcome elements of the standardized
The Guidelines Oversight Committee (GOC) at CHEST appointed the
questions and the study design ). We followed standard
editor for the guideline update. Then, the editor nominated the project
processes (duplicate independent work with agreement checking and
executive committee, the chair, and the remaining panelists (see
disagreement resolution) for title and abstract screening, full text
Acknowledgments section). The GOC approved all panelists after
screening, data abstraction, and risk of bias assessment. We
review of their qualifications and conflict of interest (COI)
abstracted data on the characteristics of: study design, participants,
disclosures. The 15 panelists include general internists, thrombosis
intervention, control, outcomes, funding, and COI. We assessed risk
specialists, pulmonologists, hematologists, and methodologists.
of bias using the Cochrane Risk of Bias Tool in randomized
Throughout guideline development, panelists were required to disclose
and an adapted tool for observational
any potential financial or intellectual conflicts of interest by topic.
When existing systematic reviews were not available or were inadequate,
Financial and intellectual conflicts of interest were classified as
we performed meta-analyses when appropriate. For each outcome of
primary (more serious) or secondary (less serious) ).
interest, we calculated the risk ratios of individual studies then pooled
Panelists with primary COIs were required to abstain from voting on
them and assessed statistical heterogeneity using the I2 statistic. We
related topic areas, but could participate in discussions provided they
used a fixed-effects model when pooling data from two trials, or when
refrained from strong advocacy.
one of the included trials was large relative to the others. Otherwise,we used a random-effects model. We used Review Manager software
Selection of Topics and Key Questions
(version 5.2) to perform the meta-analyses and construct forest plots.
First, we listed all of the topic areas from AT9 and added potential new
We calculated absolute effects by applying pooled relative risks to
topics proposed by the panel members. Next, all panel members voted
baseline risks, ideally estimated from valid prognostic observational
on whether each topic should be included in the update. Finally, the
data or, in the absence of the latter, from control group risks. When
full panel reviewed the results of the vote and decided on the final
credible data from prognostic observational studies were not
list. The panel selected a total of 15 topics: 12 "update topics" from
available, we used risk estimates from control groups of RCTs
AT9 and 3 "new topics." For each topic, we developed standardized
included in the meta-analyses ().
questions in the Population, Intervention, Comparator, Outcomeformat ().
Assessing Quality of Evidence
Based on the Grades of Recommendations, Assessment, Development,and Evaluation (GRADE) approach, quality of evidence (also known as
Systematic Search
certainty of evidence) is defined as the extent to which our confidence
Systematic methods were used to search for evidence for each question.
in the effect estimate is adequate to support a recommendation.The
When available, the National Library of Medicine's medical subject
quality of evidence is categorized as high (A level), moderate (B level),
headings keyword nomenclature was used. We searched MEDLINE
or low (includes very low) (C level).The rating of the quality of
via PubMed for original studies and the Cochrane Library for
evidence reflects the strengths and limitations of the body of
systematic reviews. For update topics, we searched the literature
evidence and was based on the study design, risk of bias,
from January 2005 to July 2014. For new topics, we searched the
imprecision, inconsistency, indirectness of results, and likelihood of
literature from 1946 (Medline inception) to July 2014. All searches
publication bias, in addition to factors specific to observational
were limited to English-language publications. We augmented
Using GRADEpro software (version 3.6), we generated
searches by checking reference lists of published articles and
tables to summarize the judgments of the quality of the evidence and
personal files, and with ongoing surveillance of the literature by
the relative and absolute effects.The GRADE tables include
Summary of Findings tables presented in the main text, and a moredetailed version called Evidence Profiles presented in the online
When we identified systematic reviews, we assessed their quality
according to the Assessment of Multiple Systematic Reviews tool.
recommendations to the supporting evidence.
We used those that were of highest quality and up to date as thesource of evidence. In the absence of a satisfactory systematicreview, we did our own evidence synthesis using the primary
Drafting of Recommendations
studies identified in AT9 and in the updated search. If the panel
Following the GRADE approach, the strength of a recommendation is
judged that the identified randomized controlled trials (RCTs) were
defined as the extent to which we can be confident that the desirable
inadequate, we expanded the search to include prospective cohort
effects of an intervention outweigh its undesirable effects. The
strength of recommendation was categorized as strong (grade 1) or
Evidence-Based Medicine
weak/conditional (grade 2). In determining the strength of the
recommendation (including quality of evidence and strength of
recommendation, the panel considered the balance of desirable and
recommendation) based on a 5-point scale derived from the GRADE
undesirable consequences (typically tradeoff between recurrent VTE
grid (strongly agree, weakly agree, neutral, weakly disagree, strongly
and bleeding events), quality of evidence, resource implications, and
Each panelist could also provide open-ended feedback on
patients' average values and preferences for different outcomes and
each recommendation with suggested wording edits or general
management options.
remarks. To achieve consensus and be included in the finalmanuscript,
The chair drafted the recommendations after the entire panel had
80% agreement (strong or weak) with a response rate of at least
75% of eligible panel members. All recommendations achieved
Recommendations were then revised over a series of conference calls
consensus in the first round. We then used an iterative approach
and through e-mail exchanges with the entire panel. A major aim
that involved review by, and approval from, all panel members for
was to ensure recommendations were specific and unambiguous.
the writing of this manuscript.
Methods for Achieving Consensus
We used a modified Delphi techniqueto achieve consensus on
External reviewers who were not members of the expert panel reviewed
each recommendation. This technique aims to minimize group
the guideline before it was published. These reviewers included content
interaction bias and to maintain anonymity among respondents.
experts, a methodological expert, and a practicing clinician. The final
Using an online survey (panelists without
manuscript was reviewed and approved by the CHEST GOC, the
a primary COI voted their level of agreement with each
CHEST Board of Regents, and the CHEST journal.
Choice of Long-Term (First 3 Months) and
with VTE without cancer; and VKA may be as effective
Extended (No Scheduled Stop Date)
as LMWH in patients without cancer. We suggested
LMWH over VKA in patients with cancer for thefollowing reasons: there is moderate-quality evidence
Summary of the Evidence
that LMWH was more effective than VKA in patients
Phases of Anticoagulant Therapy for VTE: The need
with cancer; there is a substantial rate of recurrent VTE
for anticoagulant therapy in patients with proximal
in patients with VTE and cancer who are treated with
DVT or PE is presented in AT9.The minimum
VKA; it is often harder to keep patients with cancer
duration of anticoagulant therapy for DVT or PE is
who are on VKA in the therapeutic range; LMWH is
usually 3 months; this period of treatment is referred
reliable in patients who have difficulty with oral therapy
to as "long-term therapy."A decision to treat patients
(eg, vomiting); and LMWH is easier to withhold or
for longer than 3 months, which we refer to as
adjust than VKA if invasive interventions are required
"extended anticoagulant therapy," usually implies that
or thrombocytopenia develops.
anticoagulant therapy will be continued indefinitely.
One new randomized trial compared LMWH
1. In patients with proximal DVT or pulmonary
(tinzaparin) with warfarin for the first 6 months of
embolism (PE), we recommend long-term (3 months)
treatment in 900 cancer patients with VTE.The
anticoagulant therapy over no such therapy (Grade 1B).
findings of this study are consistent with evidence inAT9 that LMWH is more effective than VKA for long-
Choice of Anticoagulant for Acute and Long-Term
term treatment of VTE, but that there is no difference
(First 3 Months) Therapy
in major bleeding or death
AT9 recommendations on choice of anticoagulant
Consequently, we still suggest VKA over LMWH in
therapy were based on comparisons of VKA with
patients without cancer, and LMWH over VKA in
LMWH that were performed in the preceding two
patients with cancer, and we have not changed our
decand with two of the NOACs (dabigatran,
assessment of the quality of evidence for either of these
rivaroxthat had recently been published.
recommendations (, ).
Although we judged that there was no convincingevidence that the efficacy of LMWH compared with
We suggested VKA therapy or LMWH over the NOACs
VKA differed between VTE patients without and with
in AT9 because only two randomized trials had
cancer, there are, nevertheless, reasons to make different
compared a NOAC (da) with
suggestions for the preferred anticoagulant in patients
VKA therapy, and none had compared a NOAC with
without and with cancer.We suggested VKA therapy
long-term LMWH. In addition, at that time, there was
over LMWH in patients without cancer for the following
little experience using a NOAC for treatment of VTE
reasons: injections are burdensome; LMWH is expensive;
and a scarcity of long-term follow-up data to support
there are low rates of recurrence with VKA in patients
their efficacy and safety. Since then, four new
TABLE 1 ] Summary of Findings: LMWH vs VKA for Long-Term Treatment of
Anticipated Absolute Effects
Risk Difference with
because of risk of bias
(from 2 fewer to 2 more)
Nonmetastatic Cancer
(from 5 fewer to 6 more)
(from 28 fewer to 35 more)
because of risk of bias
11 fewer per 1,000
(from 5 fewer to 15 fewer)
28 fewer per 1000
(from 14 fewer to 39 fewer)
70 fewer per 1,000
(from 34 fewer to 98 fewer)
because of imprecision
3 fewer per 1,000
(from 9 fewer to 6 more)
11 fewer per 1,000
(from 35 fewer to 26 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumedrisk in the comparison group and the relative effect of the intervention (and its 95% CI). CATCH ¼ Comparison of Acute Treatments in Cancer Haemostasis; GRADE ¼ Grades ofRecommendations, Assessment, Development, and Evaluation; LITE ¼ Long-term Innovations in Treatment program; LMWH ¼ low-molecular-weight heparin; RIETE ¼ RegistroInformatizado de Enfermedad Tromboembolica; RR ¼ risk ratio; UFH ¼ unfractionated heparin; VKA ¼ vitamin K antagonist. GRADE Working Group grades of evidence: Highquality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on ourconfidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate ofeffect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
aThe initial parenteral anticoagulation was similar in both arms for all except 1 study (Hull et in which patients randomized to LMWH received initially the same LWMH,whereas patients randomized to VKA initially received UFH.
bThe relative effect (RR; 95% CI) of LMWH vs VKA was assessed, and compared, in the subgroup of trials that enrolled patients without (Hull et al[LITE], Lopez-Beret et aland with (Deitcher et [ONCENOX], Hull et [LITE], Lee et [CLOT], Lee et al[CATCH], Lopez-Beret et Meyer et alcancer: Recurrent VTE: cancer RR 0.59(0.44-0.78) vs no cancer RR 0.99 (0.46-2.13); P ¼ .21 for subgroup difference. Major bleeding: cancer RR 0.96 (0.65-1.42) vs no cancer RR 0.43 (0.17 -1.17); P ¼ .14 for subgroupdifference. All-cause mortality: cancer RR 1.00 (0.88-1.33) vs no cancer RR 1.85 (0.59-5.77); P ¼ .29 for subgroup difference.
cOne study did not report deaths, which is unusual and could reflect selective reporting of outcomes.
dLow corresponds to patients without cancer and patients with nonmetastatic cancer. High corresponds to patients with metastatic cancer. These control event rates were derived fromthe Computerized Registry of Patients with Venous Thromboembolism (RIETE) registry, an ongoing prospective registry of consecutive patients with acute VTE) (Prandoni et al).
eNone of the studies was blinded, whereas the diagnosis of recurrent VTE has a subjective component and there could be a lower threshold for diagnosis of recurrent VTE in VKA-treated patients because switching the treatment of such patients to LMWH is widely practiced. At the same time, there is reluctance to diagnose recurrent VTE in patients whoare already on LMWH because there is no attractive alternative treatment option.
fRisk of recurrent VTE: Low corresponds to patients without cancer (3% estimate taken from recent large RCTs of acute treatment), intermediate to patients with local or recentlyresected cancer (appears to be consistent with Prandoni [particularly if low risk is increased to 4%]), and high to patients with locally advanced or distant metastatic cancer(Prandoni et algCI includes both no effect and harm with LMWH.
h95% CIs for the risk ratio for major bleeding includes a potentially clinically important increase or decrease with LMWH, and may also vary with the dose of LMWH used duringthe extended phase of therapyiRisk of bleeding: Low corresponds to patients without risk factor for bleeding (ie, > 75 years, cancer, metastatic disease; chronic renal or hepatic failure; platelet count <80,0000;requires antiplatelet therapy; history of bleeding without a reversible cause) (Prandoni et al,Byeth et alBibliography: Deitcher et al(ONCENOX), Hull et (LITE),Hull et al(LITE Home), Lee et al(CLOT), Lopaciuk et Lopez-Beret et al,Meyer et Romera et Lee et al(CATCH)
Evidence-Based Medicine
TABLE 2 ] Summary of Findings: Dabigatran vs VKA for Long-Term Treatment of
Anticipated Absolute Effects
Risk Difference with
Dabigatran (95% CI)
0 fewer per 1,000
(from 6 fewer to 9
(from 5 fewer to 13
5 fewer per 1,000
(from 10 fewer to 2
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). RE-COVER I ¼ Efficacy and Safety ofDabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism; RE-COVER II ¼ Phase III Study TestingEfficacy & Safety of Oral Dabigatran Etexilate vs Warfarin for 6 m Treatment for Acute Symptomatic Venous Thromboembolism. See legend forexpansion of other abbreviations and GRADE Working Group grades of evidence.
aPatients with acute VTE treated initially with LMWH or UFH.
bDabigatran 150 mg twice daily vs warfarin.
cCI includes values suggesting no effect and values suggesting either benefit or harm.
dPooled analysis of Schulman et (RE-COVER I) and Schulman et (RE-COVER II) performed by Schulman et
randomized trials have compared a NOAC (withor
reduction for recurrent VTE with different NOACs has
withoutinitial heparin therapy) with VKA therapy
not been directly compared but, based on indirect
(with initial heparin therapy) for the acute and long-
comparisons, appears to be similar to all of the NO;
term treatment of VTThe findings of these
(5) the risk of bleeding with the NOACs, and particularly
studies have been analyzed in a number of systematic
intracranial bleeding, is less with the NOACs than with
revincluding a network meta-analyIn
VKA (6) based on patients with atrial
addition, there is now extensive clinical experience using
fibrillation, GI bleeding may be higher with dabigatran,
NOACs in patients with VTE and atrial fibrillation. For
rivaroxaban, and edoxaban than with VKA therapy,
the comparison of each of the NOACs with VKA in the
although this has not been seen in patients with
initial and long-term treatment of VTE, current
VTE; (7) based on indirect comparisons, the
evidence for efficacy is moderate or high quality, for
risk of bleeding may be lower with apixaban than with the
safety (risk of bleeding) is moderate or high quality, and
other NOACsand (8) despite the lack of specific
overall is moderate or high quality (,
reversal agents for the NOACs, the risk that a major bleed
will be fatal appears to be no higher for the NOACs thanfor VKA therapy.Based on less bleeding with
In the 10th Edition of the Antithrombotic Guideline
NOACs and greater convenience for patients and health-
(AT10), the panel's overall assessment of the relative
care providers, we now suggest that a NOAC is used in
efficacy and risk of bleeding with different anticoagulant
preference to VKA for the initial and long-term treatment
agents is that: (1) the risk reduction for recurrent VTE
of VTE in patients without cancer. Factors that may
with all of the NOACs appears to be similar to the risk
influence which anticoagulant is chosen for initial and
reduction with including in patients with
long-term treatment of VTE are summarized in .
canc; (2) in patients with VTE and cancer, the risk
This decision is also expected to be sensitive to patient
reduction for recurrent VTE appears to be greater with
preferences. The order of our presentation of the NOACs
LMWH than with VKA thera; (3) the risk
(dabigatran, rivaroxaban, apixaban, edoxaban) is based
reduction for recurrent VTE with the NOACs compared
on the chronology of publication of the phase 3 trials in
to LMWH has not been assessed but, based on indirect
VTE treatment and should not be interpreted as the
comparisons, LMWH may be more effective that the
guideline panel's order of preference for the use of these
NOACs in patients with VTE and cancer(4) the risk
TABLE 3 ] Summary of Findings: Rivaroxaban vs LMWH and VKA for Acute and Long-Term Treatment of
Anticipated absolute effects
No. of Participants
Risk with LMWH and
Risk difference with
Rivaroxaban (95% CI)
1 fewer per 1,000
(from 6 fewer to 6
2 fewer per 1,000
(from 7 fewer to 5
8 fewer per 1,000
(from 3 fewer to 11
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). EINSTEIN-DVT ¼ Oral Direct Factor XaInhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in PatientsWith Acute Symptomatic Pulmonary Embolism. See legend for expansion of other abbreviations and GRADE Working Group grades of evidence.
aIncluded patients had acute, symptomatic, objectively verified proximal DVT of the legs or PE (unprovoked, 73%; cancer, 5%; previous VTE, 19%).
bRivaroxaban 20 mg daily for 6 or 12 mo after initial long-term therapy.
cCI includes values suggesting no effect and values suggesting either benefit or harm.
dPooled analysis of Bauersachs et al(EINSTEIN-DVT) and Buller et (EINSTEIN-PE) performed by Prins et Bibliography: Prins et al
*2. In patients with DVT of the leg or PE and no
Remarks: Initial parenteral anticoagulation is given
cancer, as long-term (first 3 months) anticoagulant
before dabigatran and edoxaban, is not given before
therapy, we suggest dabigatran, rivaroxaban, apix-
rivaroxaban and apixaban, and is overlapped with VKA
aban, or edoxaban over vitamin K antagonist (VKA)
therapy. See text for factors that influence choice of
therapy (all Grade 2B).
For patients with DVT of the leg or PE and no cancer
In patients with VTE and cancer ("cancer-associated
who are not treated with dabigatran, rivaroxaban,
thrombosis"), as noted earlier in this section, we still
apixaban, or edoxaban, we suggest VKA therapy over
suggest LMWH over VKA. In patients with VTE and
LMWH (Grade 2C).
cancer who are not treated with LMWH, we do not have
TABLE 4 ] Summary of Findings: Apixaban vs LMWH and VKA for Acute and Long-Term Treatment of
Anticipated Absolute Effects
Quality of the Evidence
Risk Difference with
Apixaban (95% CI)
4 fewer per 1,000
(from 9 fewer to 4
4 fewer per 1,000
(from 11 fewer to 5
13 fewer per 1,000
(from 8 fewer to 15fewer)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AMPLIFY ¼ Apixiban for the InitialManagement of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; PE ¼ pulmonary embolism. See legend for expansion ofother abbreviations and GRADE Working Group grades of evidence.
aApixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 mo.
bSubcutaneous enoxaparin, followed by warfarin.
cCI includes values suggesting no effect and values suggesting either benefit or harm. Bibliography: Agnelli et al(AMPLIFY)
Evidence-Based Medicine
TABLE 5 ] Summary of Findings: Edoxaban vs VKA for Acute and Long-Term Treatment of VTE
Anticipated Absolute Effects
Risk Difference with
Edoxaban (95% CI)
(from 6 fewer to 10 more)
6 fewer per 1,000
(from 15 fewer to 7 more)
2 fewer per 1,000
(from 6 fewer to 3 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). See and legends for expansion ofabbreviations and GRADE Working Group grades of evidence.
aPatients with acute VTE who had initially received heparin.
bEdoxaban 60 mg once daily, or 30 mg once daily if patients with creatinine clearance of 30 to 50 mL/min or a body weight below 60 kg.
cCI includes values suggesting no effect and values suggesting either benefit or harm.
dDeath, with PE not ruled out. Bibliography: Buller et al(Hokusai-VTE study)
a preference for either an NOAC or VKA. In the absence
(, ).Extended treatment with
of direct comparisons between NOACs, and no convincing
indirect evidence that one NOAC is superior to another,
reduces recurrent VTE without being associated with
we do not have a preference for one NOAC over another
much bleeding ().These
NOAC. Factors that may influence which anticoagulant
studies provide moderate quality evidence that
is chosen for initial and long-term treatment of VTE
dabigatran is as effective and as safe as VKA for
are summarized in . This decision is also expected
extended treatment of VTE (, ) and
to be sensitive to patient preferences.
provide moderate quality evidence that each of theNOACs are effective at preventing recurrent VTE
*3. In patients with DVT of the leg or PE and cancer
without being associated with a high risk of bleeding
("cancer-associated thrombosis"), as long-term (first
3 months) anticoagulant therapy, we suggest LMWH
In AT9, we suggested that if a decision was made to
over VKA therapy (Grade 2C), dabigatran (Grade
use extended treatment of VTE, the same
2C), rivaroxaban (Grade 2C), apixaban (Grade 2C),
anticoagulant should be used as was used for the initial
or edoxaban (Grade 2C).
treatment period. Our intention then was to indicatethat there was no obligation to switch from one
Remarks: Initial parenteral anticoagulation is given before
anticoagulant to a different one after 3 or 6 months of
dabigatran and edoxaban, is not given before rivaroxaban
treatment (eg, from LMWH to VKA in patients with
and apixaban, and is overlapped with VKA therapy. See
VTE and cancer). We have revised the wording of this
text for factors that influence choice of therapy.
recommendation to make it clearer that we neitherencourage nor discourage use of the same
Choice of anticoagulant for extended therapy (after
anticoagulant for initial and extended therapy.
3 months and no scheduled stop date)
Although we anticipate that the anticoagulant that was
When AT9 was written, other than a comparison of low-
used for initial treatment will often also be used for the
and standard-intensity anticoagulant therapy,there
extended therapy, if there are reasons to change the
were no comparisons of different types of extended
type of anticoagulant, this should be done. We also
therapy. Since AT9, dabigatran has been compared with
note that whereas apixaban 5 mg twice daily is used for
VKA therapy for extended treatment of VTE and found
long-term treatment, apixaban 2.5 mg twice daily is
to be similarly effective but associated with less bleeding
used for extended therapy.
TABLE 6 ] Factors That May Influence Which Anticoagulant Is Chosen for Initial and Long-Term Treatment of VTE
Preferred Anticoagulant
Qualifying Remarks
More so if: just diagnosed, extensive VTE, metastatic cancer,
very symptomatic; vomiting; on cancer chemotherapy.
Parenteral therapy to be
Rivaroxaban; apixaban
VKA, dabigatran, and edoxaban require initial parenteral
Once daily oral therapy
Rivaroxaban; edoxaban;
Liver disease and
NOACs contraindicated if INR raised because of liver disease;
VKA difficult to control and INR may not reflectantithrombotic effect.
Renal disease and
NOACs and LMWH contraindicated with severe renal
impairment. Dosing of NOACs with levels of renal impairment
clearance <30 mL/min
differ with the NOAC and among jurisdictions.
Coronary artery disease
VKA, rivaroxaban,
Coronary artery events appear to occur more often with
apixaban, edoxaban
dabigatran than with VKA. This has not been seen with theother NOACs, and they have demonstrated efficacy forcoronary artery disease. Antiplatelet therapy should beavoided if possible in patients on anticoagulants because ofincreased bleeding.
Dyspepsia or history of GI
Dabigatran increased dyspepsia. Dabigatran, rivaroxaban, and
edoxaban may be associated with more GI bleeding thanVKA.
INR monitoring can help to detect problems. However, some
patients may be more compliant with a NOAC because it isless complex.
Thrombolytic therapy use
Greater experience with its use in patients treated with
thrombolytic therapy
Reversal agent needed
Pregnancy or pregnancy
Potential for other agents to cross the placenta
Cost, coverage, licensing
Varies among regions and
INR ¼ International Normalized Ratio; NOAC ¼ non-vitamin K oral coagulant. See legend for expansion of other abbreviations.
*4. In patients with DVT of the leg or PE who receive
"indefinite"; no scheduled stopping date) therapy.
extended therapy, we suggest that there is no need to
These four options were assessed in four subgroups of
change the choice of anticoagulant after the first
VTE patients with different estimated risks of recurrence
3 months (Grade 2C).
after stopping anticoagulant therapy: (1) VTE provokedby surgery (a major transient risk factor; 3% recurrence
Remarks: It may be appropriate for the choice of
at 5 ; (2) VTE provoked by a nonsurgical
anticoagulant to change in response to changes in the
transient risk factor (eg, estrogen therapy, pregnancy, leg
patient's circumstances or preferences during the long-
injury, flight of >8 h; 15% recurrence at 5 year
term or extended phases of treatment.
(3) unprovoked (also termed "idiopathic") VTE; notmeeting criteria for provoked by a transient risk factor
Duration of Anticoagulant Therapy
or by cancer (30% recurrence at 5 ; and(4) VTE associated with cancer (also termed "cancer-
Summary of the Evidence
associated thrombosis"; 15% annualized risk of
AT9 recommendations on how long VTE should be
recurrence; recurrence at 5 years not estimated because
treated were based on comparisons of four durations of
of high mortality from cancRecurrence risk was
treatment: (1) 4 or 6 weeks; (2) 3 months; (3) longer
further stratified by estimating the risk of recurrence
than 3 months but still a time-limited course of therapy
after: (1) an isolated distal DVT was half that after a
(usually 6 or 12 months); or (4) extended (also termed
proximal DVT or PEand (2) a second unprovoked
Evidence-Based Medicine
TABLE 7 ] Summary of Findings: Dabigatran vs VKA for Extended Treatment of ,,
Anticipated Absolute Effects
No. of Participants
Risk Difference with
Dabigatran (95% CI)
All-cause mortality
1 fewer per 1,000
(from 7 fewer to 9 more)
(from 3 fewer to 20 more)
8 fewer per 1,000
(from 13 fewer to 0 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). REMEDY ¼ Secondary Prevention of VenousThrombo Embolism. See and legends for expansion of other abbreviations and GRADE Working Group grades of evidence.
aIncluded patients had acute, symptomatic, objectively verified proximal DVT of the legs or PE.
bDabigatran 150 mg twice daily taken orally for 6 mo after an initial treatment with LMWH or IV UFH.
cWarfarin adjusted to achieve an INR of 2.0-3.0 for 6 mo after an initial treatment with LMWH or IV UFH.
dActive-Control study outcomes used from Schulman et (REMEDY).
eAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Modified intention-to-treat analysis. 1.1% loss tofollow-up. Not stopped early for benefit.
fCI includes values suggesting no effect and values suggesting either benefit or harm.
gPrimary end point was composite of recurrent or fatal VTE or unexplained death. Bibliography: Schulman et al(REMEDY)
proximal DVT or PE was 50% higher (1.5-fold) than
patient's risk of bleeding on anticoagulant therapy as low
after a first unprovoked For the decision
(no bleeding risk factors; 0.8% annualized risk of
about whether to stop treatment at 3 months or to treat
major bleeding), moderate (one bleeding risk factor;
indefinitely ("extended treatment"), we categorized a
1.6% annualized risk of major bleeding), or high (two or
TABLE 8 ] Summary of Findings: Dabigatran vs Placebo for Extended Treatment of VTE,,
Anticipated Absolute Effects
No. of Participants
Risk Difference with
Dabigatran (95% CI)
All-cause mortality
51 fewer per 1,000
(from 42 fewer to 55 fewer)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). RESONATE ¼ Twice-daily Oral DirectThrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE. See and legends for expansion of otherabbreviations and GRADE Working Group grades of evidence.
aPatients with VTE who had completed at least 3 initial mo of therapy.
bDabigatran 150 mg twice daily.
cPlacebo-control study outcomes used from Schulman et (RESONATE).
dEvent rate low in a large sample size.
eEvent rate with dabigatran was 0/681 (0%); event rate with placebo was 2/662 (0.3%); anticipated absolute effect–risk difference with dabigatran is 3fewer per 1,000 (from 11 fewer to 3 more).
fEvent rate with dabigatran was 2/681 (0.3%); event rate with placebo was 0/662 (0%); anticipated absolute effect–risk difference with dabigatran is 3more per 1,000 (from 3 fewer to 11 more). Bibliography: Schulman et al(RESONATE)
TABLE 9 ] Summary of Findings: Rivaroxaban vs Placebo for Extended Treatment of
Anticipated Absolute Effects
Risk Difference with
Risk with Placebo
Rivaroxaban (95% CI)
2 fewer per 1,000
(from 3 fewer to 15 more)
57 fewer per,1000
(from 42 fewer to 64 fewer)
Moderatebecause of risk
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). See and legends for expansion ofother abbreviations and GRADE Working Group grades of evidence.
aPatients who had completed 6 to 12 mo of treatment for VTE.
bRivaroxaban 20 mg daily or placebo, specific to the continued treatment study.
cCI includes values suggesting no effect and values suggesting either benefit or harm.
dEvent rate with rivaroxaban was 4/598 (0.67%); event rate with placebo was 0/590 (0%); anticipated absolute effect–risk difference with rivaroxaban is 4more per 1,000 (from 1 less to 17 more). Bibliography: Bauersachs et (EINSTEIN-Extension)
more bleeding risk factors; $6.5% annualized risk of
Comparison of Different Time-Limited Durations of
major bleeding) A VKA targeted to an
Anticoagulation Since AT9: Two additional studies
International Normalized Ratio (INR) of about 2.5 was
have compared two time-limited durations of
the anticoagulant in all studies that compared different
anticoagulant therapyIn patients with a first
time-limited durations of therapy. We, therefore,
unprovoked PE who had completed 6 months of VKA
assumed that VKA therapy was the anticoagulant when
therapy (target INR 2.5), the Extended Duration of Oral
we were making our AT9 recommendations, including
Anticoagulant Therapy After a First Episode of
for the comparison of extended therapy with stopping
Idiopathic Pulmonary Embolism: a Randomized
treatment at 3 months.
Controlled Trial (PADIS) study randomized patients to
TABLE 10 ] Summary of Findings: Apixaban vs Placebo for Extended Treatment of VTE
Anticipated Absolute Effects
No. of Participants
Risk Difference with
Apixaban (95% CI)
All-cause mortality
9 fewer per 1,000
(from 14 fewer to 4 more)
71 fewer per 1,000
(from 59 fewer to 78 fewer)
2 fewer per 1,000
(from 4 fewer to 8 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). See and legends for expansion ofabbreviations and GRADE Working Group grades of evidence.
aPatients with VTE who had completed 6 to 12 mo of anticoagulation therapy.
bApixaban 2.5 mg twice-daily dose vs placebo.
cSignificantly wide CIs, including appreciable benefit /harm and no effect line.
dLow number of events. Bibliography: Agnelli et a(AMPLIFY-EXT)
Evidence-Based Medicine
TABLE 11 ] Risk Factors for Bleeding with
of metastatic disease; platelet count); (2) temporal relationships
Anticoagulant Therapy and Estimated Risk
(eg, interval from surgery or a previous bleeding episode); and (3) how
of Major Bleeding in Low-, Moderate-, and
effectively a previous cause of bleeding was corrected (eg, upper GI
High-Risk categories
bleeding).
cImportant for parenteral anticoagulation (eg, first 10 d), but less
important for long-term or extended anticoagulation.
dAlthough there is evidence that risk of bleeding increases with the
prevalence of risk factors,the
categorization scheme suggested here has not been validated. Further-
Previous bleeding
more, a single risk factor, when severe, will result in a high risk of bleeding(eg, major surgery within the past 2 d; severe thrombocytopenia).
eCompared with low-risk patients, moderate-risk patients are assumed to
Metastatic cancer
have a twofold risk and high-risk patients are assumed to have aneightfold risk of major
fWe estimate that anticoagulation is associated with a 2.6-fold increase in
major bleeding based on comparison of extended anticoagulation with noextended anticoagulation (Table 6 in ). The relative risk of major
bleeding during the first 3 mo of therapy may be greater that during
extended VKA therapy because: (1) the intensity of anticoagulation with
initial parenteral therapy may be greater that with VKA therapy; (2)anticoagulant control will be less stable during the first 3 mo; and (3)
predispositions to anticoagulant-induced bleeding may be uncovered
Antiplatelet therapy
during the first 3 mo of therapy.However, studies of patientswith acute coronary syndromes do not suggest a higher than 2.6 relative
Poor anticoagulant control
risk of major bleeding with parenteral anticoagulation (eg, UFH, LMWH)
Comorbidity and reduced functional capacity
compared with control.g1.6% corresponds to the average of major bleeding with initial UFH or
LMWH therapy followed by VKA therapy (Table 7 in AT9We estimated
baseline risk by assuming a 2.6 relative risk of major bleeding withanticoagulation (footnote f).
hConsistent with frequency of major bleeding observed by Hull in "high-
Nonsteroidal anti-inflammatory drug
iOur estimated baseline risk of major bleeding for low-risk patients (and
Categorization of Risk of
adjusted up for moderate- and high-risk groups as per footnote e).
jConsistent with frequency of major bleeding during prospective studies of
Estimated Absolute Risk of Major
extended anticoagulation for VTE (Table 6 in AT9
another 18 months of treatment or to placebo, and then
followed both groups of patients for an additional
24 months after study drug was stopped
The study's findings were consistent withour recommendations in AT9; the additional 18 months
Baseline risk (%)
of VKA was very effective at preventing recurrent VTE
but, once anticoagulation was stopped, the risk of
recurrent VTE was the same in those who had been
treated for 6 or for 24 months. This new information has
after first 3 mo
not increased the quality of evidence for comparison of a
Baseline risk (%/y)
longer vs a shorter, time-limited course of
anticoagulation in patients without cancer.
In patients with a
first proximal DVT or PE and active
cancer who had residual DVT on US imaging after
AT9 ¼ 9th Edition of the Antithrombotic Guideline.
completing 6 months of LMWH therapy, the Cancer-
From AT9. Since AT9, references for bleeding with individual factors have
been nonsteroidal anti-in
Duration of Anticoagulation based on Compression
flammatory drug has been
added as a risk factor; a systematic review has described the risk in VTE
Ultrasonography (DACUS) study randomized patients
trial patients who were randomized to no antithrombotic therapy; and
to another 6 months of LMWH or to stop therapy and
several recent publications have compared clinical prediction rules forbleeding in various populations.
followed patients for 12 months after they stopped
bMost studies assessed risk factors for bleeding in patients who were on
LMWHThe additional 6 months of LMWH reduced
VKA therapy. The risk of bleeding with different anticoagulants is not
recurrent VTE but, once anticoagulation was stopped,
addressed in this table. The increase in bleeding associated with a riskfactor will vary with: (1) severity of the risk factor (eg, location and extent
the risk of recurrent VTE was the same in those who had
TABLE 12 ] Summary of Findings: 6, 12, or 24 mo vs 3 or 6 mo as Minimum Duration of Anticoagulation for ,
Anticipated Absolute Effects
No. of Participants
Risk Difference with E
xtended Use (95% CI)
16 more per 1,000
(from 4 fewer to 46 more)
18 fewer per 1,000
(from 40 fewer to 8 more)
(from 1 fewer to 27 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). DACUS ¼ Warfarin Optimal Duration ItalianPulmonary Embolism; DOTAVK ¼ Durée Optimale du Traitement AntiVitamines K; WODIT-DVT ¼ Warfarin Optimal Duration Italian Deep Vein Thrombosis;WODIT-PE ¼ Warfarin Optimal Duration Italian Pulmonary Embolism. See , and legends for expansion of other abbreviations and GRADEWorking Group grades of evidence.
aStudies vary in follow-up duration (10 mo-3 y) and in duration of time-limited VKA (3-6 mo).
bVKA as NOACs are not included.
cTiming of randomization relative to the start of treatment and length of treatment varied across studies: Pinede et and Campbell et randomizedat diagnosis; and Agnelli et Eischer et and Couturaud et alrandomized after the initial 3 mo (Agnelli et al) or 6 mo (Eischer et alCouturaud et al) of treatment to stop or continued treatment. The longer duration of treatment was 6 mo in Agnelli et (provoked PE) andPinede et 12 mo in Agnelli et al(unprovoked DVT; unprovoked PE), 24 mo in Couturaud et al,and 30 mo in Eischer et Generally, studydesign was strong. No study stopped early for benefit; 3 stopped early because of slow recruitment (Campbell et Pinede et al,Eischer et al) and 1because of lack of benefit (Agnelli et In 1 study (Campbell et al), 20% of VTE outcomes were not objectively confirmed. Patients and caregivers wereblinded in Couturaud et al,but none of the other studies was. Adjudicators of outcomes were blinded in all but 1 study (Campbell et All studies usedeffective randomization concealment, intention-to-treat analysis, and a low unexplained dropout frequency.
dStudy populations varied across studies: Pinede et alenrolled provoked and unprovoked proximal DVT and PE; Campbell et enrolled provoked andunprovoked isolated distal DVT, proximal DVT, and PE; Agnelli et had separate randomizations for provoked PE (3 vs 6 mo) and unprovoked (3 vs 12mo); Agnelli et enrolled unprovoked proximal DVT; Eischer et alenrolled unprovoked isolated DVT, proximal DVT, and PE with high levels of factorVIII; and Couturaud et aenrolled unprovoked PE.
eCIs include both values suggesting no effect and values suggesting either benefit or harm. Bibliography: Campbell et Pinede et (DOTAVK), Agnelliet (WODIT-PE Provoked and Unprovoked), Agnelli et (WODIT-DVT), Couturaud et al(PADIS-PE), Siragusa et al(DACUS), Eischer et al(AUREC-FVIII)
been treated for 6 or for 12 months. In the same study,
stopped) in the PADIS supports AT9 estimates
all patients without residual DVT after 6 months of
for the efficacy of extended VKA therapy.
LMWH stopped therapy and had a low risk ofrecurrence during the next year (three episodes in 91
Since AT9, two additional studies have compared
patients). This study's findings have not changed our
extended NOAC therapy (daapixaban
recommendations for treatment of VTE in patients with
with stopping treatment (ie, placebo). These two studies,
and the previous study that evaluated extendedtreatment with rivaroxaban, found that extended
Evaluations of Extended Anticoagulant Therapy Since
therapy with these three NOAC regimens reduced
AT9: When AT9 was written, extended treatment of
recurrent VTE by at least 80% and was associated with a
VTE with VKA therapy had been evaluated in six
modest risk of bleeding , ).
studies (mostly patients with unprovoked proximal
These three studies, however, enrolled heterogeneous
DVT or PEor a second episode of VTE), and
populations of patients (ie, not confined to unprovoked
with an NOAC (rivaroxaban vs placebo) in one study of
VTE) and only followed patients for 6 to 12 months,
heterogeneous patients.Since AT9, no studies have
which limits the implications of their findings in
compared extended VKA therapy with stopping
relationship to extended therapy.
anticoagulants, although the large reduction in recurrentVTE with 18 additional months of VKA therapy
When considering the risks and benefits of extended
compared with placebo (ie, before study drug was
anticoagulation in this update, the AT10 panel decided
Evidence-Based Medicine
to use the same estimates for the reduction in recurrent
how to use D-dimer testing and a patient's sex to make
VTE and the increase in bleeding with anticoagulation
decisions about extended therapy in patients with a first
that we used in AT9, and that were based on VKA
unprovoked VTE, we have not made recommendations
therapy. Our reasoning was: (1) VKA is still widely used
based on these factors.
for extended treatment of VTE; (2) we felt that there was
Revised Recommendations: These are unchanged from
not enough evidence of differences in efficacy and
AT9 with one minor exception. A qualifying remark has
bleeding during extended therapy to justify separate
been added to the recommendation that suggests extended
recommendations for NOACs, either as a group or as
therapy over stopping treatment at 3 months in patients
individual agents; and (3) our recommendations about
with a first unprovoked proximal DVT or PE and a low or
whether or not to use extended therapy were not
moderate risk of bleeding; this remark notes that patient
sensitive to assuming that there was a one-third
sex and D-dimer level measured a month after stopping
reduction in bleeding with extended therapy compared
anticoagulant therapy may influence this treatment
with the estimated risk of bleeding with extended
decision. If it becomes clear that, during the extended
therapy that are shown in and were used in
phase of treatment, there are important differences in
AT9 (eg, with a NOAC compared with VKA)
the risk of recurrence or bleeding with the different
(the only recommendation to change would be a strong
anticoagulant agents, agent-specific recommendations
instead of a weak recommendation in favor of extended
for extended therapy may become justified.
therapy in patients with a second unprovoked VTE whohad a moderate risk of bleeding).
5. In patients with a proximal DVT of the leg orPE provoked by surgery, we recommend treatment
Better Selection of Patients for Extended VTE
with anticoagulation for 3 months over (i) treatment
Therapy: The most common and difficult decision
of a shorter period (Grade 1B), (ii) treatment of a
about whether to stop anticoagulants after a time-
longer, time-limited period (eg, 6, 12, or 24 months)
limited course or to use extended therapy is in patients
(Grade 1B), or (iii) extended therapy (no scheduled
with a first unprovoked proximal DVT or PE without a
stop date) (Grade 1B).
high risk of bleeding. In this subgroup of patients,patient sex and D-dimer level measured about 1 month
6. In patients with a proximal DVT of the leg or PE
after stopping anticoagulant therapy can help to further
provoked by a nonsurgical transient risk factor, we
stratify the risk of recurrent VTE.Men have about
recommend treatment with anticoagulation for
a 75% higher (1.75-fold) risk of recurrence compared
3 months over (i) treatment of a shorter period
with women, whereas patients with a positive D-dimer
(Grade 1B) and (ii) treatment of a longer time-limited
result have about double the risk of recurrence
period (eg, 6, 12, or 24 months) (Grade 1B). We
compared with those with a negative D-dimer, and
suggest treatment with anticoagulation for 3 months
the predictive value of these two factors appears to be
over extended therapy if there is a low or moderate
additive. The risk of recurrence in women with a
bleeding risk (Grade 2B), and recommend treatment
negative posttreatment D-dimer appears to be similar
for 3 months over extended therapy if there is a high
to the risk that we have estimated for patients with a
risk of bleeding (Grade 1B).
proximal DVT or PE that was provoked by a minor
Remarks: In all patients who receive extended
transient risk factor (approximately 15% recurrence at
anticoagulant therapy, the continuing use of treatment
5 years); consequently, the argument for extended
should be reassessed at periodic intervals (eg, annually).
anticoagulation in these women is not strong, suggestingthat D-dimer testing will often influence a woman's
7. In patients with an isolated distal DVT of the leg
decision. The risk of recurrence in men with a negative
provoked by surgery or by a nonsurgical transient
D-dimer is not much less than the overall risk of
risk factor, we suggest treatment with anticoagulation
recurrence that we have estimated for patients with an
for 3 months over treatment of a shorter period
unprovoked proximal DVT or PE (approximately
(Grade 2C); we recommend treatment with
25% compared with approximately 30% recurrence at 5
anticoagulation for 3 months over treatment of a
years); consequently, the argument for extended
longer, time-limited period (eg, 6, 12, or 24 months)
anticoagulation in these men is still substantial,
(Grade 1B); and we recommend treatment with
suggesting that D-dimer testing will often not influence
anticoagulation for 3 months over extended therapy
a male's decision. Because there is still uncertainty about
(no scheduled stop date) (Grade 1B).
Remarks: Duration of treatment of patients with isolated
Remarks: In all patients who receive extended
distal DVT refers to patients in whom a decision has
anticoagulant therapy, the continuing use of treatment
been made to treat with anticoagulant therapy; however,
should be reassessed at periodic intervals (eg, annually).
it is anticipated that not all patients who are diagnosed
11. In patients with DVT of the leg or PE and active
with isolated distal DVT will be prescribed
cancer ("cancer-associated thrombosis") and who
(i) do not have a high bleeding risk, we recommend
8. In patients with an unprovoked DVT of the leg
extended anticoagulant therapy (no scheduled stop
(isolated distal or proximal) or PE, we recommend
date) over 3 months of therapy (Grade 1B), and
treatment with anticoagulation for at least 3 months
(ii) have a high bleeding risk, we suggest extended
over treatment of a shorter duration (Grade 1B), and
anticoagulant therapy (no scheduled stop date) over
we recommend treatment with anticoagulation for
3 months of therapy (Grade 2B).
3 months over treatment of a longer, time-limited
Remarks: In all patients who receive extended
period (eg, 6, 12, or 24 months) (Grade 1B).
anticoagulant therapy, the continuing use of treatment
Remarks: After 3 months of treatment, patients with
should be reassessed at periodic intervals (eg, annually).
unprovoked DVT of the leg or PE should be evaluatedfor the risk-benefit ratio of extended therapy. Duration
Aspirin for Extended Treatment of VTE
of treatment of patients with isolated distal DVT refers
Summary of the Evidence
to patients in whom a decision has been made to treatwith anticoagulant therapy; however, it is anticipated
AT9 did not address if there was a role for aspirin, or
that not all patients who are diagnosed with isolated
antiplatelet therapy generally, in the treatment of VTE.
distal DVT will be prescribed anticoagulants.
Since then, two randomized trials have compared aspirinwith placebo for the prevention of recurrent VTE in
*9. In patients with a first VTE that is an unpro-
patients with a first unprovoked proximal DVT or PE
voked proximal DVT of the leg or PE and who have a
who have completed 3 to 18 months of anticoagulant
(i) low or moderate bleeding risk (see text), we
therapyThese trials provide moderate-quality
suggest extended anticoagulant therapy (no sched-
evidence that extended aspirin therapy reduces recurrent
uled stop date) over 3 months of therapy (Grade 2B),
VTE by about one-third. In these trials, the benefits of
and a (ii) high bleeding risk (see text), we recom-
aspirin outweighed the increase in bleeding, which was
mend 3 months of anticoagulant therapy over
not statistically significant The
extended therapy (no scheduled stop date)
two trials enrolled patients with a first unprovoked VTE
who did not have an increased risk of bleeding; patientsfor whom these guidelines have suggested extended
Remarks: Patient sex and D-dimer level measured a
anticoagulant therapy. Extended anticoagulant therapy
month after stopping anticoagulant therapy may
is expected to reduce recurrent VTE by more than
influence the decision to stop or extend anticoagulant
80% and extended NOAC therapy may be associated
therapy (see text). In all patients who receive
with the same risk of bleeding as aspirin.If patients
extended anticoagulant therapy, the continuing use of
with a first unprovoked VTE decline extended
treatment should be reassessed at periodic intervals
anticoagulant therapy because they have risk factors for
(eg, annually).
bleeding or because they have a lower than average riskof recurrence, the net benefit of aspirin therapy is
10. In patients with a second unprovoked VTE
expected to be less than in the two trials that evaluated
and who have a (i) low bleeding risk (see text), we
aspirin for extended treatment of VTE.
recommend extended anticoagulant therapy (noscheduled stop date) over 3 months (Grade 1B);
Based on indirect comparisons, we expect the net benefit
(ii) moderate bleeding risk (see text), we suggest
of extended anticoagulant therapy in patients with
extended anticoagulant therapy over 3 months of
unprovoked VTE to be substantially greater than the
therapy (Grade 2B); or (iii) high bleeding risk
benefits of extended aspirin therapy.Consequently, we
(see text), we suggest 3 months of anticoagulant
do not consider aspirin a reasonable alternative to
therapy over extended therapy (no scheduled stop
anticoagulant therapy in patients who want extended
date) (Grade 2B).
therapy. However, if a patient has decided to stop
Evidence-Based Medicine
TABLE 13 ] Summary of Findings: Aspirin vs Placebo for Extended Treatment of VTE
Anticipated Absolute Effects
Risk with Control
Risk Difference with Aspirin (95% CI)
1 fewer per 1,000
(from 3 fewer to 3 more)
60 fewer per 1,000
(from 24 fewer to 89 fewer)
(from 6 fewer to 29 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ASPIRE ¼ Aspirin to Prevent RecurrentVenous Thromboembolism; HR ¼ hazard ratio; INSPIRE ¼ International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism;WARFASA ¼ Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin) study. See legend for expansion of otherabbreviations and GRADE Working Group grades of evidence.
aThe Brighton et study was stopped early and included only one-third of the intended patients.
bCI includes values suggesting no effect and values suggesting either benefit or harm.
cEstimate based on Simes et al(INSPIRE) of synthesis of Brighton et al(ASPIRE) and Becattini et al(WARFASA).
dEstimate taken from Douketis et Bibliography: Simes et al(INSPIRE)
anticoagulants, prevention of recurrent VTE is one of
Whether and How to Prescribe Anticoagulants
the benefits of aspirin (may also include reductions in
to Patients With Isolated Distal DVT
arterial thrombosis and colon cancer) that needs to be
Summary of the Evidence
balanced against aspirin's risk of bleeding andinconvenience. Use of aspirin should also be reevaluated
AT9 discouraged routine whole-leg US examinations
when patients with VTE stop anticoagulant therapy
(ie, including the distal veins) in patients with suspected
because aspirin may have been stopped when
DVT, thereby reducing how often isolated distal DVT is
anticoagulants were started (, ).
diagnosThe rationale for not routinely examiningthe distal veins in patients who have had proximal DVT
*12. In patients with an unprovoked proximal DVT
excluded is that: (1) other assessment may already
or PE who are stopping anticoagulant therapy and
indicate that isolated distal DVT is either unlikely to be
do not have a contraindication to aspirin, we suggest
present or unlikely to cause complications if it is present
aspirin over no aspirin to prevent recurrent VTE
(eg, low clinical probability of DVT, D-dimer is
negative); (2) if these conditions are not met, a repeat USexamination of the proximal veins can be done after a
Remarks: Because aspirin is expected to be much less
week to detect possible DVT extension and the need for
effective at preventing recurrent VTE than
treatment; and (3) false-positive findings for DVT occur
anticoagulants, we do not consider aspirin a reasonable
more often with US examinations of the distal compared
alternative to anticoagulant therapy in patients who want
with the proximal veins.
extended therapy. However, if a patient has decided tostop anticoagulants, prevention of recurrent VTE is one of
If the calf veins are imaged (usually with US) and
the benefits of aspirin that needs to be balanced against
isolated distal DVT is diagnosed, there are two
aspirin's risk of bleeding and inconvenience. Use of
management options: (1) treat patients with
aspirin should also be reevaluated when patients stop
anticoagulant therapy or (2) do not treat patients with
anticoagulant therapy because aspirin may have been
anticoagulant therapy unless extension of their DVT is
stopped when anticoagulants were started.
detected on a follow-up US examination (eg, after 1 and
2 weeks, or sooner if there is concern; there is no widely
deep veins for 2 weeks over anticoagulation (Grade 2C),
accepted protocol for surveillance US Because
and (ii) with severe symptoms or risk factors for
about 15% of untreated isolated distal DVT are expected
extension (see text), we suggest anticoagulation over
to subsequently extend into the popliteal vein and may
serial imaging of the deep veins (Grade 2C).
cause PE, it is not acceptable to neither anticoagulate nor
Remarks: Patients at high risk for bleeding are more
do surveillance to detect thrombus extension.
likely to benefit from serial imaging. Patients who place
In AT9, we judged that there was high-quality evidence
a high value on avoiding the inconvenience of repeat
that anticoagulant therapy was effective for the
imaging and a low value on the inconvenience of
treatment of proximal DVT and PE, but uncertainty that
treatment and on the potential for bleeding are likely to
the benefits of anticoagulation outweigh its risks in
choose initial anticoagulation over serial imaging.
patients with isolated distal DVT because of their lower
14. In patients with acute, isolated, distal DVT of
risk of progressive or recurrent VTE. We suggest the
the leg who are managed with anticoagulation, we
following as risk factors for extension of distal DVT
recommend using the same anticoagulation as for
that would favor anticoagulation over surveillance:
patients with acute proximal DVT (Grade 1B).
(1) D-dimer is positive (particularly when markedlyso without an alternative reason); (2) thrombosis is
15. In patients with acute, isolated, distal DVT of
extensive (eg, >5 cm in length, involves multiple veins,
the leg who are managed with serial imaging, we
>7 mm in maximum diameter); (3) thrombosis is
(i) recommend no anticoagulation if the thrombus
close to the proximal veins; (4) there is no reversible
does not extend (Grade 1B), (ii) suggest anticoagulation
provoking factor for DVT; (5) active cancer; (6) history
if the thrombus extends but remains confined to
of VTE; and (7) inpatient status.We consider
the distal veins (Grade 2C), and (iii) recommend
thrombosis that is confined to the muscular veins of the
anticoagulation if the thrombus extends into the
calf (ie,, soleus, gastrocnemius) to have a lower risk of
proximal veins (Grade 1B).
extension than thrombosis that involves the axial(ie, true deep; peroneal, tibial) veins.Severe
CDT for Acute DVT of the Leg
symptoms favor anticoagulation, a high risk for bleeding() favors surveillance, and the decision to use
Summary of the Evidence
anticoagulation or surveillance is expected to be sensitive
At the time of AT9, there was one small randomized
to patient preferences. We anticipate that isolated distal
trialcomparing the effect of CDT vs anticoagulant
DVT that are detected using a selective approach to
alone on development of PTS, and another larger
whole-leg US will often satisfy criteria for initial
randomized trial (Catheter-Directed Venous
anticoagulation, whereas distal DVT detected by routine
Thrombolysis in Acute Iliofemoral Vein Thrombosis
whole-leg US often will not.
[CAVENT] Study) assessing short-term (eg, venous
The updated literature search did not identify any new
patency and bleeding) but not long-term (eg, PTS)
randomized trials that assessed management of patients
outcomes.The CAVENT Study has since reported
with isolated distal DVT. Two new systematic
that CDT reduced PTS, did not alter quality of life, and
reviewsand a narrative reviewaddressed
appears to be cost-effective
treatment of isolated distal DVT. In addition to
A retrospective analysis found that CDT (3649
summarizing available data, consistent with AT9, they
patients) was associated with an increase in transfusion
emphasize the limitations of available evidence. In the
(twofold), intracranial bleeding (threefold), PE
absence of substantive new evidence, the panel endorsed
(1.5-fold), and vena caval filter insertion (twofold);
the AT9 recommendations without revision. The
long-term outcomes and PTS were not reported.
evidence supporting these recommendations remains
A single-center prospective registry found that
low quality because it is not based on direct comparisons
US-assisted CDT in acute iliofemoral (87 patients)
of the two management strategies, and ability to predict
achieved high rates of venous patency, was rarely
extension of distal DVT is limited.
associated with bleeding, and that only 6% of patientshad PTS at 1 y
13. In patients with acute isolated distal DVT of theleg and (i) without severe symptoms or risk factors for
This new evidence has not led to a change in our
extension (see text), we suggest serial imaging of the
recommendation for the use of CDT in patients with
Evidence-Based Medicine
TABLE 14 ] Summary of Findings: Catheter-Assisted Thrombus Removal vs Anticoagulation Alone for Acute Leg DVT
Anticipated Absolute Effects
Risk Difference with Catheter-Assisted
Thrombus Removal (95% CI)
26 fewer per 1,000
(from 43 fewer to 54 more)
Moderate-Risk Population
19 fewer per 1,000
(from 34 fewer to 12 more)
Moderate-Risk Population
194 more per 1,000
(from 17 fewer to 1000 more)
Moderate-Risk Population
153 fewer per 1,000
(from 265 fewer to 0 more)
191 more per 1,000
(from 41 more to 386 more)
The mean quality of life in the
intervention groups was 0.2 higher
(2.8 lower to 3 higher)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CAVENT ¼ Catheter-Directed VenousThrombolysis in Acute Iliofemoral Vein Thrombosis; EQ-5D ¼ EuroQol – 5 Dimensions; PTS ¼ postthrombotic syndrome; QoL ¼ quality of life. See and legends for expansion of other abbreviations and GRADE Working Group grades of evidence.
aCI includes values suggesting both benefit and harm.
bLow number of events.
cReported deaths from Enden et al(CAVENT).
dEstimate taken from Watson et al.The 1 study included for this outcome was Enden et (CAVENT).
eBaseline risks for nonfatal recurrent VTE and for major bleeding derived from Douketis et fMost of bleeding events occur during the first 7 d.
gThis estimate is based on the Watson et al.The 1 study included for this outcome was Enden et (CAVENT). For PTS at 6 mo, published data fromEnden et (CAVENT) provide an estimate RR of 0.93 (0.61-1.42) via Watson et al.hThis estimate is based on the findings of the VETO
iFor severe PTS, assuming the same RR of 0.46 and a baseline risk of the absolute reduction is 75 fewer severe PTS per 1,000 (from 29 fewer to138 fewer) over 2 y.
jReported patency from Enden et al(CAVENT).
kOpen-label.
lDisease-specific QoL (VEINES-QOL) estimate used at 24 mo according to treatment allocation.
mGeneric QoL (EQ-5D) at 24 mo according to treatment allocation estimate is mean difference 0.04 (-0.01 to 0.17). Bibliography: Watson et alused for alloutcomes except patency and QoL; Enden et used for patency estimates; Enden et used for QoL estimates.
DVT. Although the quality of the evidence has
CDT have iliofemoral DVT, symptoms for <14 days,
improved, the overall quality is still low because of very
good functional status, life expectancy of $1 year, and a
serious imprecision. Unchanged from AT9, we propose
low risk of bleeding and , ).
that the patients who are most likely to benefit from
Because the balance of risks and benefits with CDT is
TABLE 15 ] Risk Factors for Bleeding With, and
thrombolytic therapy in 5 clinical trials, the following factors were indepen-
Contraindications to Use of, Thrombolytic
dently associated with moderate or severe bleeding: older age (OR, 1.04 per
Therapy (Both Systemic and Locally
year); black (OR, 1.4); female (OR, 1.5); hypertension (OR, 1.2); lower weight
(OR, 0.99 per kg).We estimate that systemic thrombolytic therapy isassociated with relative risk of major bleeding of 3.5 within 35 d
Major Contraindicatio
(RR, approximately 7 for intracranial bleeding); about three-quarters of theexcess of major bleeds with thrombolytic therapy occur in the first 24 h
Structural intracranial disease
Previous intracranial hemorrhage
Ischemic stroke within 3 mo
uncertain, we consider that anticoagulant therapy alone
is an acceptable alternative to CDT in all patients with
Recent brain or spinal surgery
acute DVT who do not have impending venous
Recent head trauma with fracture or brain injury
Bleeding diathesis
16. In patients with acute proximal DVT of the leg,
we suggest anticoagulant therapy alone over CDT
Systolic BP >180
Diastolic BP >110
Recent bleeding (nonintracranial)
Remarks: Patients who are most likely to benefit from
CDT (see text), who attach a high value to prevention of
Recent invasive procedure
PTS, and a lower value to the initial complexity, cost,
Ischemic stroke more than 3 mo previously
and risk of bleeding with CDT, are likely to choose CDT
Anticoagulated (eg, VKA therapy)
over anticoagulation alone.
Traumatic cardiopulmonary resuscitation
Pericarditis or pericardial fluid
Role of IVC Filter in Addition to
Diabetic retinopathy
Anticoagulation for Acute DVT or PE
Summary of the Evidence
Low body weight (eg, <60 kg)
Our recommendation in AT9 was primarily based on
findings of the Prevention du Risque d'Embolie
Pulmonaire par Interruption Cave (PREPIC) randomizedtrialwhich showed that placement of a permanent
See and legends for expansion of abbreviations and GRADE
IVC filter increased DVT, decreased PE, and did not
Working Group grades of evidence.
aThe presence of major contraindications usually precludes use of
influence VTE (DVT and PE combined) or mortality. Since
thrombolytic therapy; consequently, these factors have not been well
then, several registries have suggested that IVC filters can
studied as risk factors for bleeding associated with thrombolytic therapy.
Patients with 1 or more major contraindication are usually considered to
reduce early mortality in patients with acute VTE, although
be "high risk for bleeding with thrombolytic therapy." The factors listed in
this evidence has been questionedThe recently
this table are consistent with other recommendations for the use of
published PREPIC 2 randomized trial found that
thrombolytic therapy in patients with PE.bRisk factors for bleeding during anticoagulant therapy that are noted
placement of an IVC filter for 3 months did not reduce
in that are not included in this table are also likely to be relative
recurrent PE, including fatal PE, in anticoagulated patients
contraindications to thrombolytic therapy. The increase in bleeding associ-
with PE and DVT who had additional risk factors for
ated with a risk factor will vary with: (1) severity of the risk factor (eg, extent oftrauma or recent surgery) and (2) temporal relationships (eg, interval from
recurrent VTE , This new evidence
surgery or a previous bleeding episode; believed to decrease markedly after
is consistent with our recommendations in AT9. However,
approximately 2 wk). Risk factors for bleeding at critical sites (eg, intracranial,
because it is uncertain if there is bene
intraocular) or noncompressible sites are stronger contraindications for
fit to placement of an
thrombolytic therapy. Depending on the nature, severity, temporality, and
IVC filter in anticoagulated patients with severe PE (eg,
number of relative contraindications, patients may be considered "high risk of
with hypotension), and this is done by some experts, our
bleeding with thrombolytic therapy" or "non-high risk for thrombolytictherapy.
recommendation against insertion of an IVC
" Patients with no risk factors, 1-2 minor risk factors (eg, female and
black race) are usually considered "low risk of bleeding with thrombolytic
patients with acute PE who are anticoagulated may not
therapy." Among 32,000 Medicare patients ($65 y) with myocardial infrac-
apply to this select subgroup of patients.
tion who were treated with thrombolytic therapy, the following factorswere independently associated with intracranial haemorrhage: age $75 y
Although the PREPIC 2 study has improved the quality of
(OR, 1.6); black (OR, 1.6); female (OR, 1.4); previous stroke (OR, 1.5);systolic BP $160 mm Hg (OR, 1.8); women #65 kg or men # 80 kg (OR, 1.5);
evidence for this recommendation, overall quality is still
INR >4 (OR, 2.2The rate of intracranial hemorrhage increased from
moderate because of imprecision ).
0.7% with 0 or 1 of these risk factors, to 4.1% with $5 risk factors. Among
The AT10 panel decided against combining the results of
32,000 patients with myocardial infraction who were treated with
Evidence-Based Medicine
TABLE 16 ] Summary of Findings: Temporary IVC Filter vs No Temporary IVC Filter in Addition to Anticoagulation
for Acute DVT or PE,
Anticipated Absolute Effects
Risk With No Temporary
IVC Filter in Addition to
Risk Difference with
Temporary IVC Filter (95% CI)
15 more per 1,000
(from 24 fewer to 96
15 more per 1,000
(from 7 fewer to 104
10 fewer per 1,000
(from 34 fewer to 49
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). IVC ¼ inferior vena cava. See and legends for expansion of other abbreviations and GRADE Working Group grades of evidence.
aAll patients received full-dose anticoagulant therapy according to guidelines for at least 6 mo.
bFilter removal was attempted in 164 patients and successful for 153 (93.3%).
cCI includes values suggesting no effect and values suggesting either benefit or harm.
dSmall number of events. Bibliography: Mismetti et (PREPIC 2)
the PREPIC and PREPIC 2 studies because of differences
The same study found that routine use of graduated
in the type of filter used, the duration of filter placement,
compression stockings did not reduce leg pain during
and differences in the length of follow-up.
the 3 months after DVT diagnosis , This finding, however, does not mean that
17. In patients with acute DVT or PE who are treated
graduated compression stockings will not reduce acute
with anticoagulants, we recommend against the use of
symptoms of DVT or chronic symptoms in those who
an IVC filter (Grade 1B).
have developed PTS.
Compression Stocking to Prevent PTS
*18. In patients with acute DVT of the leg, we sug-gest not using compression stockings routinely to
Summary of the Evidence
prevent PTS (Grade 2B).
AT9 suggested routine use of graduated compressionstockings for 2 years after DVT to reduce the risk of PTS.
Remarks: This recommendation focuses on prevention
That recommendation was mainly based on findings of two
of the chronic complication of PTS and not on the
small, single-center, randomized trials in which patients
treatment of symptoms. For patients with acute or
and study personnel were not blinded to stocking use (no
chronic symptoms, a trial of graduated compression
placebo stocking).The quality of the evidence was
stockings is often justified.
moderate because of risk of bias resulting from a lack ofblinding of an outcome (PTS) that has a large subjective
Whether to Treat Subsegmental PE
component and because of serious imprecision of thecombined findings of the two trials , ).
Summary of the Evidence
Since AT9, a much larger multicenter, placebo-controlled
Subsegmental PE refers to PE that is confined to the
trial at low risk of bias found that routine use of graduated
subsegmental pulmonary arteries. Whether these
compression stockings did not reduce PTS or have other
patients should be treated, a question that was not
important benefits.Based on this trial, we now suggest
addressed in AT9, has grown in importance because
that graduated compression stockings not be used
improvements in CT pulmonary angiography have
routinely to prevent PTS and consider the quality to the
increased how often subsegmental PE is diagnosed
evidence to be moderate ).
(ie, from approximately 5% to more than 10% of
TABLE 17 ] Summary of Findings: Elastic Compression Stockings vs No Elastic Compression Stockings to Prevent
Anticipated Absolute Effects
Risk with No Elastic
Risk Difference with Elastic
Compression Stockings
Compression Stockings (95% CI)
(from 67 fewer to 86 more)
34 fewer per 1,000
(from 97 fewer to 65 more)
The mean acute leg pain
The mean acute leg pain in
in the control groups
the intervention groups
was 1.13 leg pain
was 0.26 higher (0.03
severity assessed
lower to 0.55 higher)
on an 11-pointnumerical painrating
The mean QoL in the
intervention groups was0.12 lower (1.11 lower to0.86 higher)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ECS ¼ elastic compression stockings; SF-36 ¼ Short Form 36. See and legends for expansion of other abbreviations and GRADE Working Group grades of evidence.
aFor included studies, number of PTS events as assessed by Villalta's criteria
bLow number of events.
cThere were 3 studies originally included for this outcome (Brandjes et Prandoni et al,and Kahn et [SOX]). There was very high heterogeneityamong the 3 studies, I2 ¼ 92% (P < .01). The pooled effect of the 3 studies was RR, 0.63 (0.35-1.13). Yet, because of the high risk of bias associated withBrandjes et and Prandoni et al,it was decided to focus on the estimate of the low-risk trial, Kahn et (SOX), which is used here.
dThis estimate is based on the findings of the VETO study.
eCI includes values suggesting no effect and values suggesting either benefit or harm.
fThere were 3 studies originally included for this outcome (Brandjes et al,Prandoni et and Kahn et [SOX]). The pooled effect of the 3 studieswas RR, 0.91 (0.65-1.27). Yet, because of the high risk of bias associated with Brandjes et aland Prandoni et al,it was decided to focus on the estimateof the low-risk trial, Kahn et al(SOX), which is used here.
gThis estimate is the mean of 2 estimates derived from 2 studies: 12.4% probable/definite and 29.1% confirmed VTE.
hWide CI that includes no effect.
iEstimate derived from Kahn et jEstimate based on VEINES-QOL score improvement of 5.8 points (SD, 7.5) for active ECS vs 5.9 (SD, 7.1) for placebo ECS.
kSF-36 physical component score improved by 8.4 points (SD, 13.6) for active ECS vs 9.9 (SD, 13.2) for placebo ECS (difference between groups of -1.53points, 95% CI, -3.44 to 0.39; P ¼ .12). Bibliography: Kahn et al(SOX) for PTS and recurrent VTE; Kahn et alfor acute leg pain
PE).There is uncertainty whether these patients
Our literature search did not identify any randomized
should be anticoagulated for two reasons. First, because
trials in patients with subsegmental PE. There is,
the abnormalities are small, a diagnosis of subsegmental
however, high-quality evidence for the efficacy and
PE is more likely to be a false-positive finding than a
safety of anticoagulant therapy in patients with larger
diagnosis of PE in the segmental or more proximal
PE, and this is expected to apply similarly to patients
pulmonary arSecond, because a true
with subsegmental PE.Whether the risk of progressive
subsegmental PE is likely to have arisen from a small
or recurrent VTE is high enough to justify
DVT, the risk of progressive or recurrent VTE without
anticoagulation in patients with subsegmental PE is
anticoagulation is expected to be lower than in patients
uncertain.There were no episodes of recurrent
with a larger PE.
VTE in retrospective reports that included about 60
Evidence-Based Medicine
patients with subsegmental PE and no proximal DVT
favors no anticoagulant therapy. The decision to
and who were not anticoagulated.However, in
anticoagulate or not is also expected to be sensitive to
another retrospective analysis, patients with
patient preferences. Patients who are not anticoagulated
subsegmental PE appeared to have a similar risk of
should be told to return for reevaluation if symptoms
recurrent VTE during 3 months of anticoagulant
persist or worsen.
therapy as patients with larger PE, and a higher risk than
The evidence supporting our recommendations is low
in patients who were suspected of having PE but had PE
quality because of indirectness and because there is
limited ability to predict which patients will have VTEcomplications without anticoagulation.
The AT10 panel endorsed that, if no anticoagulanttherapy is an option, patients with subsegmental PE
*19. In patients with subsegmental PE (no
should have bilateral US examinations to exclude
involvement of more proximal pulmonary arteries)
proximal DVT of the DVT should also be
and no proximal DVT in the legs who have a (i)
excluded in other high-risk locations, such as in upper
low risk for recurrent VTE (see text), we suggest
extremities with central venous catheters. If DVT is
clinical surveillance over anticoagulation (Grade
detected, patients require anticoagulation. If DVT is not
2C), and (ii) high risk for recurrent VTE (see text),
detected, there is uncertainty whether patients should be
we suggest anticoagulation over clinical surveillance
anticoagulated. If a decision is made not to
anticoagulate, there is the option of doing one or morefollow-up US examinations of the legs to detect (and
Remarks: US imaging of the deep veins of both legs
then treat) evolving proximal DVT.Serial testing
should be done to exclude proximal DVT. Clinical
for proximal DVT has been shown to be a safe
surveillance can be supplemented by serial US imaging
management strategy in patients with suspected PE who
of the proximal deep veins of both legs to detect evolving
have nondiagnostic ventilation-perfusion scans, many of
DVT (see text). Patients and physicians are more likely
whom are expected to have subsegmental PE.
to opt for clinical surveillance over anticoagulation if
We suggest that a diagnosis of subsegmental PE is more
there is good cardiopulmonary reserve or a high risk of
likely to be correct (ie, a true positive) if: (1) the CT
pulmonary angiogram is of high quality with goodopacification of the distal pulmonary arteries; (2) there
Treatment of Acute PE Out of the Hospital
are multiple intraluminal defects; (3) defects involvemore proximal subsegmental arteries (ie, are larger);
Summary of the Evidence
(4) defects are seen on more than one image; (5) defects
Our recommendation in AT9 was based on: (1) two
are surrounded by contrast rather than appearing to be
trials that randomized patients with acute PE to receive
adherent to the pulmonary artery walls; (6) defects are
LMWH for only 3 days in the hospitalor entirely at
seen on more than one projection; (7) patients are
homecompared with being treated with LMWH in
symptomatic, as opposed to PE being an incidental
the hospital for a longer period; (2) 15 observational
finding; (8) there is a high clinical pretest probability for
studies, 9 of which were prospective, that evaluated
PE; and (9) D-dimer level is elevated, particularly if the
treatment of acute PE out of the hospitaland
increase is marked and otherwise unexplained.
(3) longstanding experience treating DVT withoutadmission to a hospital. Since AT9, no further
In addition to whether or not patients truly have
randomized trials have evaluated out-of-hospital
subsegmental PE, we consider the following to be risk
treatment of acute PE. Several additional prospective
factors for recurrent or progressive VTE if patients are
and retrospective observational studies have reported
not anticoagulated—patients who: are hospitalized or
findings consistent with earlier reports, and the findings
have reduced mobility for another reason; have active
of all of these studies have been included in recent meta-
cancer (particularly if metastatic or being treated with
analyses that have addressed treatment of acute PE out
chemotherapy); or have no reversible risk factor for VTE
of the hospital.
such as recent surgery. Furthermore, a lowcardiopulmonary reserve or marked symptoms that
Studies that evaluated NOACs for the acute treatment of
cannot be attributed to another condition favor
PE did not report the proportion of patients who were
anticoagulant therapy, whereas a high risk of bleeding
treated entirely out of hospital, but it is probable that
this was uncommon. Treatment of acute PE with a
dying from PE and the highest risk of bleeding obtain
NOAC that does not require initial heparin therapy
the least net benefit from thrombolytic therapy and are
(eg, rivaroxaban, apixaban) facilitates treatment without
likely to be harmed.
hospital admission. Consistent with AT9, we suggest
Evidence for the Use of Thrombolytic Therapy in
that patients who satisfy all of the following criteria are
Patients With Acute PE: AT9 recommendations for the
suitable for treatment of acute PE out of the hospital:
use of thrombolytic therapy in acute PE were based on
(1) clinically stable with good cardiopulmonary reserve;
low-quality evidence.At that time, only about 800
(2) no contraindications such as recent bleeding, severe
patients with acute PE had been randomized to receive
renal or liver disease, or severe thrombocytopenia
thrombolytic therapy or anticoagulant therapy alone and,
(ie, <70,000/mm3); (3) expected to be compliant with
consequently, estimates of efficacy, safety, and overall
treatment; and (4) the patient feels well enough to be
mortality were very imprecise. In addition, the trials that
treated at home. Clinical decision rules such as the
enrolled these 800 patients had a high risk of bias and
Pulmonary Embolism Severity Index (PESI), either the
there was a strong suspicion that there was selective
original form with score <85 or the simplified form with
reporting of studies that favored thrombolytic therapy
score of 0, can help to identify low-risk patients who are
(ie, publication bias). Randomized trials have clearly
suitable for treatment at home.However, we
established that thrombolytic therapy increases bleeding
consider clinical prediction rules as aids to decision-
in patients with acute myocardial infarction,but that
making and do not require patients to have a predefined
evidence was indirect when applied to patients with PE.
score (eg, low-risk PESI score) to be considered fortreatment at home. Similarly, although we do not
Since AT9, two additional small, randomized trials
suggest the need for routine assessment in patients with
and a much larger trialhave evaluated systemic
acute PE, we agree that the presence of right ventricular
thrombolytic therapy in about 1,200 patients with acute
dysfunction or increased cardiac biomarker levels should
PE. The findings of these new studies have been
discourage treatment out of the hospitThe
combined with those of earlier studies in a number of
quality of the evidence for treatment of acute PE at
meta-analyses.These new data, by reducing
home remains moderate because of marked imprecision.
imprecision for estimates of efficacy and safety and the
The updated recommendation has been modified to
overall risk of bias, have increased the quality of the
state that appropriately selected patients may be treated
evidence from low to moderate for recommendations
entirely at home, rather than just be discharged early.
about the use of systemic thrombolytic therapy in acutePE (, ).
*20. In patients with low-risk PE and whose homecircumstances are adequate, we suggest treatment at
Most of the new evidence comes from the Pulmonary
home or early discharge over standard discharge
Embolism Thrombolysis trial, which randomized 1,006
(eg, after the first 5 days of treatment) (Grade 2B).
patients with PE and right ventricular dysfunction totenecteplase and heparin or to heparin therapy alone(with placeThe most notable findings of this
Systemic Thrombolytic Therapy for PE
study were that thrombolytic therapy prevented
Summary of the Evidence
cardiovascular collapse but increased major (includingintracranial) bleeding; these benefits and harms were
It has long been established that systemic thrombolytic
finely balanced, with no convincing net benefit from
therapy accelerates resolution of PE as evidenced by
thrombolytic therapy. An additional finding was that
more rapid lowering of pulmonary artery pressure,
"rescue thrombolytic therapy" appeared to be of benefit
increases in arterial oxygenation, and resolution of
in patients who developed cardiovascular collapse after
perfusion scan defects, and that this therapy increases
initially being treated with anticoagulant therapy alone.
bleeding.The net mortality benefit of thrombolytictherapy in patients with acute PE, however, has been
Management Implication of the Updated Evidence:
uncertain and depends on an individual patient's
The improved quality of evidence has not resulted in
baseline (ie, without thrombolytic therapy) risk of dying
substantial changes to our recommendations because:
from acute PE and risk of bleeding. Patients with the
(1) the new data support that the benefits of systemic
highest risk of dying from PE and the lowest risk of
thrombolytic therapy in patients without hypotension,
bleeding obtain the greatest net benefit from
including those with right ventricular dysfunction or an
thrombolytic therapy. Patients with the lowest risk of
increase in cardiac biomarkers ("intermediate-risk PE"),
Evidence-Based Medicine
TABLE 18 ] Summary of Findings: Systemic Thrombolytic Therapy vs Anticoagulation Alone for Acute PE
Anticipated Absolute Effects
Risk Difference with Systemic
Thrombolytic Therapy (95% CI)
18 fewer per 1,000
(from 5 fewer to 26 fewer)
18 fewer per 1,000
(from 8 fewer to 24 fewer)
54 more per 1,000
(from 29 more to 87 more)
(from 2 more to 21 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) isbased on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). See and legends for expansion ofabbreviations and GRADE Working Group grades of evidence.
aLow number of events.
bEstimate from Chatterjee et al.Other estimates from meta-analyses on this topic include Dong et OR, 0.89 (0.45-1.78); Cao et RR, 0.64(0.29-1.40); Marti et al:OR, 0.59 (0.36-0.96); Nakamura et RR, 0.72 (0.39-1.31); Chatterjee et (intermediate-risk PE only): OR, 0.46(0.25-0.92); Marti et al(intermediate-risk PE only): OR, 0.42 (0.17-1.03).
cMajority (83%) of participants in Chatterjee et alwere "moderate" risk.
dEstimate from Chatterjee et Other estimates from meta-analyses on this topic include Dong et OR, 0.63 (0.33-1.20); Cao et al:RR 0.44(0.19-1.05); Marti et al:OR, 0.50 (0.27-0.94); Nakamura et al:RR, 0.60 (0.21-1.69).
eEstimate from Chatterjee et Other estimates from meta-analyses on this topic include Dong et OR, 1.61 (0.91-2.86); Cao et al: RR, 1.16(0.51-2.60); Marti et al:OR, 2.91 (1.95-4.36); Nakamura et al:RR, 2.07 (0.58-7.35).
fEstimate from Chatterjee et al.Bibliography: Chatterjee et
are largely offset by the increase in bleeding; and
PE Without Hypotension: Consistent with AT9, we
(2) among patients without hypotension, it is still not
recommend that most patients with acute PE who do
possible to confidently identify those who will derive net
not have hypotension are not treated with thrombolytic
benefit from this therapy.
therapy. However, patients with PE withouthypotension include a broad spectrum of presentations.
PE With Hypotension: Consistent with AT9, we suggest
At the mild end of the spectrum are those who have
that patients with acute PE with hypotension (ie, systolic
minimal symptoms and minimal cardiopulmonary
BP <90 mm Hg for 15 min) and without high bleeding
impairment. As noted in the section "Setting for initial
risk () are treated with thrombolytic therapy.
anticoagulation for PE," many of these patients can be
The more severe and persistent the hypotension, and the
treated entirely at home or can be discharged after a
more marked the associated features of shock and
brief admission. At the severe end of the spectrum are
myocardial dysfunction or damage, the more compelling
those with severe symptoms and more marked
the indication for systemic thrombolytic therapy.
cardiopulmonary impairment (even though systolic
Conversely, if hypotension is transient or less marked,
BP is >90 mm Hg). In addition to clinical features
not associated with features of shock or myocardial
of cardiopulmonary impairment (eg, heart rate, BP,
dysfunction, and if there are risk factors for bleeding,
respiratory rate, jugular venous pressure, tissue
physicians and patients are likely to initially choose
hypoperfusion, pulse oximetry), they may have
anticoagulant therapy without thrombolytic therapy. If
evidence of right ventricular dysfunction on their CT
thrombolytic therapy is not used and hypotension
pulmonary angiogram or on echocardiography, or
persists or becomes more marked, or clinical features of
evidence of myocardial damage as reflected by
shock or myocardial damage develop or worsen,
increases in cardiac biomarkers (eg, troponins, brain
thrombolytic therapy may then be used.
We suggest that patients without hypotension who are
impairment should be monitored closely for
at the severe end of the spectrum be treated with
deterioration. Development of hypotension suggests that
aggressive anticoagulation and other supportive
thrombolytic therapy has become indicated.
measures, and not with thrombolytic therapy. These
Cardiopulmonary deterioration (eg, symptoms, vital
patients need to be closely monitored to ensure that
signs, tissue perfusion, gas exchange, cardiac
deteriorations are detected. Development of hypotension
biomarkers) that has not progressed to hypotension may
suggests that thrombolytic therapy has become
also alter the risk-benefit assessment in favor of
indicated. Deterioration that has not resulted in
thrombolytic therapy in patients initially treated with
hypotension may also prompt the use of thrombolytic
therapy. For example, there may be a progressive
Catheter-Based Thrombus Removal for the
increase in heart rate, a decrease in systolic BP
Initial Treatment of PE
(which remains >90 mm Hg), an increase in jugularvenous pressure, worsening gas exchange, signs of
Summary of the Evidence
shock (eg, cold sweaty skin, reduced urine output,
Interventional catheter-based treatments for acute PE
confusion), progressive right heart dysfunction on
include delivery of CDT if there is not a high risk of
echocardiography, or an increase in cardiac biomarkers.
bleeding, or catheter-based treatment without
We do not propose that echocardiography or cardiac
thrombolytic therapy if there is a high risk of bleeding.
biomarkers are measured routinely in all patients withPE, or in all patients with a non–low-risk PESI
CDT: The most important limitation of systemic
assessmenThis is because, when measured
thrombolytic therapy is that it increases bleeding,
routinely, the results of these assessments do not have
including intracranial bleeding. CDT, because it uses a
clear therapeutic implications. For example, we do not
lower dose of thrombolytic drug (eg, about one-third),
recommend thrombolytic therapy routinely for patients
is expected to cause less bleeding at remote sites
without hypotension who have right ventricular
(eg, intracranial, CDT, however, may be
dysfunction and an increase in cardiac biomarkers.
as or more effective than systemic thrombolytic therapy
However, we encourage assessment of right ventricular
for two reasons: (1) it achieves a high local concentration
function by echocardiography and/or measurement of
of thrombolytic drug by infusing drug directly into
cardiac biomarkers if, following clinical assessment,
the PE and (2) thrombus fragmentation resulting from
there is uncertainty about whether patients require more
placement of the infusion catheter in the thrombus or
intensive monitoring or should receive thrombolytic
additional maneuvers, or an increase in thrombus
permeability from US delivered via the catheter, mayenhance endogenous or pharmacologic thrombolysis.
21. In patients with acute PE associated with
Thrombolytic therapy is usually infused over many
hypotension (eg, systolic BP < 90 mm Hg) who do not
hours or overnight. In emergent situations, systemic
have a high bleeding risk, we suggest systemically
thrombolytic therapy can be given while CDT is being
administered thrombolytic therapy over no such
arranged, and active thrombus fragmentation and
therapy (Grade 2B).
aspiration (see below) can be combined with CDT.
*22. In most patients with acute PE not associated
A single randomized trial of 59 patients found that,
with hypotension, we recommend against systemi-
compared with anticoagulation alone, US-assisted CDT
cally administered thrombolytic therapy (Grade 1B).
improved right ventricular function at 24 h.Observational studies also suggest that CDT is effective
*23. In selected patients with acute PE who
at removing thrombus, lowering pulmonary arterial
deteriorate after starting anticoagulant therapy but
pressure, and improving right ventricular function
have yet to develop hypotension and who have a low
without being associated with a high risk of
bleeding risk, we suggest systemically administered
bleedinMost of these studies are small (fewer
thrombolytic therapy over no such therapy
than 30 patients) and retrospective, although a recent
prospective registry of 101 patients and a prospectivecohort study of 150 patients also support the efficacy of
Remarks: Patients with PE and without hypotension
CDT.Whereas there was no major bleeding in the
who have severe symptoms or marked cardiopulmonary
registry, there were 15 episodes in the cohort study
Evidence-Based Medicine
(10%; no intracranial or fatal bleeds). An older
expertise and resources are available, we suggest
randomized trial of 34 patients with massive PE found
catheter-assisted thrombus removal over no such
that infusion of recombinant tissue plasminogen
intervention (Grade 2C).
activator into a pulmonary artery as opposed to aperipheral vein did not accelerate thrombolysis, but
Remarks: Catheter-assisted thrombus removal refers to
caused more frequent bleeding at the catheter insertion
mechanical interventions, with or without catheter
sitNo randomized trials or observational studies
have compared contemporary CDT with systemicthrombolytic therapy. For patients who requirethrombolytic therapy and do not have a high risk of
Pulmonary Thromboendarterectomy in for the
bleeding, the AT10 panel favored systemic thrombolytic
Treatment of Chronic Thromboembolic
therapy over CDT because, compared with
Pulmonary Hypertension
anticoagulation alone, there is a higher quality ofevidence in support of systemic thrombolytic therapy
Summary of the Evidence
than for CDT.
The AT9 recommendation was based on case series thathave shown marked improvements in cardiopulmonary
Catheter-Based Thrombus Removal Without
status after thromboendarterectomy in patients with
Thrombolytic Therapy: Catheter-based mechanical
chronic thromboembolic pulmonary hypertension
techniques for thrombus removal involve thrombus
(CTEPH).Although additional case series have
fragmentation using various types of catheters, some of
been reported, the quality of the evidence for
which are designed specifically for this purpos
thromboendarterectomy in patients with CTEPH has
Fragmentation results in distal displacement of
not improved.The AT10 panel decided,
thrombus, with or without suctioning and removal of
however, that our previous recommendation for
some thrombus through the catheter. Mechanical
thromboendarterectomy in selected patients with
methods alone are used when thrombus removal is
CTEPH was too restrictive and could contribute to
indicated but there is a high risk of bleeding that
suboptimal evaluation and treatment of patients with
precludes thrombolytic therapy. No randomized trial or
CTEPH. For example, because of improvements in
prospective cohort studies have evaluated catheter-based
surgical technique, it is now often possible to remove
thrombus removal of PE without thrombolytic therapy.
organized thrombi from peripheral pulmonary arteries.
Evidence for the use of CDT compared with
In patients with inoperable CTEPH or persistent
anticoagulation alone, CDT compared with systemic
pulmonary hypertension after pulmonary
thrombolytic therapy, and catheter-based treatment
thromboendarterectomy, there is new evidence from a
without thrombolytic therapy is of low quality and our
randomized trial that pulmonary vasodilator therapy
recommendations are weak.
may be of benefit.For these reasons, we no longeridentify central disease as a selection factor for
*24. In patients with acute PE who are treated with a
thromboendarterectomy in patients with CTEPH, and
thrombolytic agent, we suggest systemic thrombo-
we emphasize that patients with CTEPH should be
lytic therapy using a peripheral vein over CDT
assessed by a team with expertise in the evaluation and
management of pulmonary hy
Remarks: Patients who have a higher risk of bleeding
*26. In selected patients with chronic thromboem-
with systemic thrombolytic therapy, and who have
bolic pulmonary hypertension (CTEPH) who are
access to the expertise and resources required to do
identified by an experienced thromboendarter-
CDT, are likely to choose CDT over systemic
ectomy team, we suggest pulmonary thromboen-
darterectomy over no pulmonarythromboendarterectomy (Grade 2C).
*25. In patients with acute PE associated with hy-potension and who have (i) a high bleeding risk,
Remarks: Patients with CTEPH should be evaluated by a
(ii) failed systemic thrombolysis, or (iii) shock that is
team with expertise in treatment of pulmonary
likely to cause death before systemic thrombolysis
hypertension. Pulmonary thromboendarterectomy is
can take effect (eg, within hours), if appropriate
often lifesaving and life-transforming. Patients with
CTEPH who are not candidates for pulmonary
with UEDVT who do not undergo thrombolysis
thromboendarterectomy may benefit from other
mechanical and pharmacological interventions designedto lower pulmonary arterial pressure.
Management of Recurrent VTE onAnticoagulant Therapy
Thrombolytic Therapy in Patients With Upper
Summary of Evidence
There are no randomized trials or prospective cohort
Summary of the Evidence
studies that have evaluated management of patients withrecurrent VTE on anticoagulant therapy. Consequently,
The AT9 recommendation was based on: (1) mostly
management is based on low-quality evidence and an
retrospective observational studies suggesting that
assessment of the probable reason for the recurrence.
thrombolysis could improve short- and long-term
Risk factors for recurrent VTE while on anticoagulant
venous patency, but a lack of data about whether
therapy can be divided into two broad categories:
thrombolysis reduced PTS of the arm; (2) occasional
(1) treatment factors and (2) the patient's intrinsic risk
reports of bleeding in patients with UEDVT who were
of recurrence. How a new event should be treated will
treated with thrombolysis, and clear evidence that
depend on the reason(s) for recurrence.
thrombolysis increases bleeding in other settings; and(3) recognition that, compared to anticoagulation alone,
Treatment Factors: The risk of recurrent VTE decreases
thrombolytic therapy is complex and We
rapidly after starting anticoagulant therapy, with a much
suggest that thrombolysis is most likely to be of benefit
higher risk during the first week (or month) compared
in patients who meet the following criteria: severe
with the second week (or month).A recurrence
symptoms; thrombus involving most of the subclavian
soon after starting therapy can generally be managed by
vein and the axillary vein; symptoms for <14 days; good
a time-limited (eg, 1 month) period of more aggressive
functional status; life expectancy of $1 year; and low
anticoagulant intensity (eg, switching from an oral agent
risk for bleeding. We also suggested CDT over systemic
back to LMWH, an increase in LMWH dose). Other
thrombolysis to reduce the dose of thrombolytic drug
treatment factors that are associated with recurrent VTE
and the risk of bleeding. There is new moderate quality
and will suggest specific approaches to management
evidence that CDT can reduce PTS of the leg
include: (1) was LMWH being used; (2) was the patient
(, ) and that systemic thrombolysis
adherent; (3) was VKA subtherapeutic; (4) was
increases bleeding in patients with acute PE,and
anticoagulant therapy prescribed correctly; (5) was the
low-quality evidence that CDT can accelerate breakdown
patient taking an NOAC and a drug that reduced
of acute PE.This evidence has indirect bearing on
anticoagulant effect; and (6) had anticoagulant dose
thrombolysis in patients with UEDVT, but it has not
been reduced (drugs other than VKA)?
changed the overall quality of the evidence or our
There is moderate-quality evidence that LMWH is more
recommendations for use of thrombolysis in these patients.
effective than VKA therapy in patients with VTE and
27. In patients with acute upper extremity DVT
cancer. A switch to full-dose LMWH, therefore, is often
(UEDVT) that involves the axillary or more proximal
made if there has been an unexplained recurrent VTE on
veins, we suggest anticoagulant therapy alone over
VKA therapy or an NOAC. If the recurrence happened
thrombolysis (Grade 2C).
on LMWH, the dose of LMWH can be increased. If thedose of LMWH was previously reduced (eg, by 25% after
Remarks: Patients who (i) are most likely to benefit
1 month of treatment), it is usually increased to the
from thrombolysis (see text); (ii) have access to CDT;
previous level. If the patient was receiving full-dose
(iii) attach a high value to prevention of PTS; and
LMWH, the dose may be increased by about 25%. In
(iv) attach a lower value to the initial complexity, cost,
practice, the increase in dose is often influenced by the
and risk of bleeding with thrombolytic therapy are likely
LMWH prefilled syringe dose options that are available.
to choose thrombolytic therapy over anticoagulation
Once-daily LMWH may also be switched to a twice-
daily regimen, particularly if two injections are required
28. In patients with UEDVT who undergo
to deliver the increase in LMWH dose. Treatment
thrombolysis, we recommend the same intensity
adherence, including compliance, can be difficult to
and duration of anticoagulant therapy as in patients
assess; for example, symptoms of a recurrent DVT may
Evidence-Based Medicine
encourage medication adherence and a return of
truly was a recurrent VTE; (2) evaluation of compliance
coagulation results to the "therapeutic range."
with anticoagulant therapy; and (3) consideration of anunderlying malignancy.
Patient Factors: The most important intrinsic riskfactor for recurrent VTE while on anticoagulant
therapy is active cancer, with an unexplained
There is substantial new evidence since AT9 about how
recurrence often pointing to yet-to-be-diagnosed
to treat VTE. This evidence led the panel to change
disease. Antiphospholipid syndrome is also associated
many of the AT9 recommendations that are included in
with recurrent VTE, either because of associated
this update, and has strengthened the evidence quality
hypercoagulability or because a lupus anticoagulant has
that underlies others that are unchanged. We now
led to underdosing of VKA because of spurious increases
suggest the use of NOACs over VKA for the treatment
in INR results. Anticoagulated patients may be taking
of VTE in patients without cancer. Although we still
medications that increase the risk of thrombosis such as
suggest LMWH as the preferred long-term treatment
estrogens or cancer chemotherapy, in which case these
for VTE and cancer, we no longer suggest VKA over
treatments may be withdrawn.
NOACs in these patients. Although we note factors in
A retrospective observational study found an acceptable
individual patients that may favor selection of one
risk of recurrence (8.6%) and major bleeding (1.4%)
NOAC over another in patients without or with cancer,
during 3 months of follow-up in 70 cancer patients
or may favor selection of either a NOAC or VKA in
with recurrent VTE while on anticoagulant therapy
patients with cancer, we have not expressed an overall
who either switched from VKA therapy to LMWH
preference for one NOAC over another, or for either
(23 patients) or had their LMWH dose increased by
a NOAC or VKA in patients with cancer, because:
about 25% (47 patients).If there is no reversible
(1) there are no direct comparisons of different
reason for recurrent VTE while on anticoagulant
NOACs; (2) NOACs have not been compared with
therapy, and anticoagulant intensity cannot be increased
VKA in a broad spectrum of patients with VTE and
because of risk of bleeding, a vena caval filter can be
cancer; and (3) indirect comparisons have not shown
inserted to prevent PE.However, it is not known if
convincingly different outcomes with different
insertion of a filter in these circumstances is worthwhile,
NOACs. Another notable change in AT10 is that,
and the AT10 panel consider this an option of last resort.
based on a new low risk of bias study, we now suggestthat graduated compression stocking are not routinely
*29. In patients who have recurrent VTE on VKA
used to prevent PTS. Recommendations that are
therapy (in the therapeutic range) or on dabigatran,
unchanged but are now supported by better evidence
rivaroxaban, apixaban, or edoxaban (and are believed
include: (1) discouragement of IVC filter use in
to be compliant), we suggest switching to treatment
anticoagulated patients; (2) encouragement of indefinite
with LMWH at least temporarily (Grade 2C).
anticoagulant therapy after a first unprovoked PE;and (3) discouragement of thrombolytic therapy in
Remarks: Recurrent VTE while on therapeutic-dose
PE patients who are not hypotensive and are not
anticoagulant therapy is unusual and should prompt the
deteriorating on anticoagulation.
following assessments: (1) reevaluation of whether theretruly was a recurrent VTE; (2) evaluation of compliance
Of the 54 recommendations that are included in the 30statements in this update, 20 (38%) are strong
with anticoagulant therapy; and (3) consideration of an
recommendations (Grade 1) and none is based on high-
underlying malignancy. A temporary switch to LMWH
quality (Grade A) evidence. The absence of high-quality
will usually be for at least 1 month.
evidence highlights the need for further research to
*30. In patients who have recurrent VTE on long-
guide VTE treatment decisions. As new evidence
term LMWH (and are believed to be compliant), we
becomes available, these guidelines will need to be
suggest increasing the dose of LMWH by about one-
updated. Goals of our group and CHEST include
quarter to one-third (Grade 2C).
transition to continually updated "living guidelines."The modular format of this update is designed to
Remarks: Recurrent VTE while on therapeutic-dose
facilitate this development, with individual topics and
anticoagulant therapy is unusual and should prompt the
questions being addressed as new evidence becomes
following assessments: (1) reevaluation of whether there
available. We will also facilitate implementation of our
recommendations into practice by developing new and
Enterprises for VTE talks. T. M. and C. S. K. have received honorariafrom Chest Enterprises for VTE Prep Courses. T. M.'s institution
convenient ways to disseminate our recommendations.
has received grant funding (no salary support) from Portola
This will enable achievement of another of our goals—
Pharmaceuticals for the Acute Medically Ill VTE Prevention With
reduction in the burden of VTE in individual patients
Extended Duration Betrixaban Study (APEX) related to extendedprophylaxis against VTE with betrixaban. T. M.'s institution received
and in the general population.
grant support from Bayer Pharmaceuticals for a research projectconcerning the etiology of chronic thromboembolic pulmonary
hypertension. He has also authored textbook chapters related tothrombolytic interventions in patients with acute PE and pulmonary
Author contributions: C. K. was the chair of the panel. C. K., E. A.,
thromboendarterectomy in chronic thromboembolic pulmonary
A. B., J. O., D. J., and L .M. were executive committee members of the
hypertension. S. M. S.'s and S. C. W.'s institution has received grant
panel. C. K. and N. S. were the topic editors for "Treatment of Acute
funding (no salary support) from the Canadian Institutes of Health
Pulmonary Embolism Out of Hospital". C. K. and D. J. were the topic
for the D-dimer Optimal Duration Study Phase II (DODS-
editors for "Pulmonary Thromboendarterectomy in the Treatment of
Extension), from Washington University via the National Institutes
Chronic Thromboembolic Pulmonary Hypertension". E. K. and A. B.
of Health (Genetic Informatics Trial), Bayer related to VTE
were the topic editors for "Compression Stocking to Prevent Post-
(EINSTEIN studies), and from Bristol-Myers Squibb related to
Thrombotic Syndrome". E. K. and A. B. were the topic editors for
apixaban for the Secondary Prevention of Thromboembolism
"Thrombolytic Therapy in Patients with Upper Extremity Deep Vein
(Apixaban for the Secondary prevention of Thromboembolism: A
Thrombosis". D. J. and C. S. K. were the topic editors for "Management
prospective Randomized Outcome pilot study among patients with
of Recurrent Venous Thromboembolism on Anticoagulant Therapy".
the AntiphosPholipid Syndrome). J. R. E. V.'s institution has received
H. B. and N. S. were the topic editors for "Whether and How to
grant funding (no salary support) from Bristol-Myers Squibb for
Anticoagulate Patients with Isolated Distal Deep Vein Thrombosis".
evaluating the role of apixaban for long-term treatment of VTE. P. W.
M. H. and H. B. were the topic editors for "Catheter-Directed
is a coinvestigator on a grant regarding the treatment of subsegmental
Thrombolysis for Acute Deep Vein Thrombosis of the Leg". M. H. and
PE. He has authored several studies and grants related to the long-
J. V. were the topic editors for "Duration of Anticoagulant Therapy".
term and extended anticoagulation (using vitamin K antagonists and
L. M. and C. S. K. were the topic editors for "Whether to Anticoagulate
the direct oral anticoagulants). P. W. has received grant funding from
Subsegmental Pulmonary Embolism". S. S., T. M. and P. W. were the
Bristol-Myers Squibb and has received honoraria for talks from
topic editors for "Catheter-Based Thrombus Removal for the Initial
Bayer. E. A. A., H. B., C. K., P. W., and S. C. W. participated in the
Treatment of Pulmonary Embolism". S.W. and T. M. were the topic
last edition of the CHEST Antithrombotic Therapy for VTE Disease
editors for "Choice of Long-Term (First 3 Months) and Extended
Guidelines (AT9). None declared (A. B., J. O., N. S.).
(No Scheduled Stop Date) Anticoagulant". S. S., S. W. and J. V. werethe topic editors for "Systemic Thrombolytic Therapy for Pulmonary
Role of sponsors: This study was funded in total by internal funds
Embolism". L. M. and P. W. were the topic editors for "Aspirin
from the American College of Chest Physicians.
for Extended Treatment of Venous Thromboembolism". L. M. and
Dedication: All of the authors would like to acknowledge the
C. S. K. were the topic editors for "Role of Inferior Vena Caval
contributions of previous authors of the CHEST Antithrombotic
Filter in Addition to Anticoagulation in Patients with Acute Deep
Vein Thrombosis or Pulmonary Embolism". E. A. and J. O. weremethodologists for the panel. A. B. was the GOC liaison to the panel.
Additional information: The e-Tables and e-Figures can be found
L. M. was an overall guideline editor.
in the Supplemental Materials section of the online article.
Financial/nonfinancial disclosures: The authors have reported toCHEST the following: In the past 3 years, E. A. A. was an author on a
number of systematic reviews on anticoagulation in patients with
cancer. H. B. has received compensation for participation on advisory
committees with speaking engagements sponsored by Sanofi-Aventis,
Bayer Healthcare, and Daiichi-Sankyo. His institution has received
grant funding (no salary support) from Daiichi-Sankyo for studying
VTE treatment. He has also served as a coauthor of original studies
using rivaroxaban (EINSTEIN, EINSTEIN Pulmonary Embolism
[PE]) and edoxaban (Hokusai-VTE study). M. H. has received grant
funding and has delivered talks related to long-term and extendedanticoagulation and treatment of subsegmental PE. He has also
authored several papers related to long-term and extended
anticoagulation, treatment of subsegmental PE, and compressionstocking in preventing postthrombotic syndrome. D. J.'s institution
has received grant funding (no salary support) from Instituto de salud
Carlos III, Sociedad Española de Neumología y Cirugía Torácica, and
NeumoMadrid for studying PE. He was a member of Steering
Committee of the Pulmonary Embolism Thrombosis Study
(PEITHO), a principal investigator of an original study related to the
role of the inferior vena cava filter in addition to anticoagulation in
patients with acute DVT or PE and has participated in the derivation
of scores for identification of low-risk PE. He has delivered talksrelated to treatment of acute PE. C. K. has been compensated for
speaking engagements sponsored by Boehringer Ingelheim and Bayer
Healthcare related to VTE therapy. His institution has received grant
funding (no salary support) from the National Institutes of Healthrelated to the topic of catheter-assisted thrombus removal in patients
with leg DVT. He has also published many studies related to long-
term anticoagulation and compression stockings in preventing
postthrombotic syndrome. L. M. has frequently lectured on the
duration of long-term anticoagulation and is a coauthor on several
risk-stratification papers. She has received honoraria from CHEST
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