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Vte
Vte
Ambulatory
Venous
Thromboembolism
Guideline Team
Patient population: Outpatient adults with suspected acute deep venous thrombosis (DVT) of the upper and lower
extremity, pulmonary embolus (PE), or both (VTE).
Objectives: (1) Improve the recognition of VTE and selection of appropriate testing. (2) Improve selection of
appropriate therapy. (3) Shorten resolution time for clinical symptoms. (4) Reduce bleeding and other
complications. (5) Reduce recurrence of VTE. (6) Reduce incidence of pulmonary embolism. (7) Reduce
Team Members
mortality. (8) Avoid preventable Emergency Department visits and hospital admissions
Brian J Brophy, MD
Key
Points
General Medicine
Initiate
treatment immediately. Patients without contraindications to anticoagulation should begin treatment at
Kirk A Frey, MD, PhD
time of diagnosis [IA*]. If PE is clinically likely, initiation of anticoagulation should not await testing; if only DVT
Nuclear Medicine
is suspected and testing will be prompt, initiation may await testing. Therapeutic levels of anticoagulation should be
James B Froehlich, MD,
MPH
achieved as quickly as possible. If warfarin is used for anticoagulation, initiate it on treatment day 1 simultaneous to
Director, Anticoagulation
initiation of low molecular weight heparin. Other oral agents may not require bridging treatment with heparin.
Services
Diagnosis
R Van Harrison, PhD
Deep venous thrombosis (lower extremity DVT)
Medical Education
Clinical likelihood estimation. Symptoms and signs alone are not adequately sensitive or specific for diagnosis
Steven Kronick, MD
or exclusion of DVT but clinical likelihood estimation based on symptoms and signs is a necessary step in the
Emergency Medicine
testing strategy [IA].
Melissa A Miller, MD,
Venous color duplex doppler ultrasound imaging. This imaging is the standard for diagnosis [IA].
MS
Pulmonary & Critical
Pulmonary embolism
Care Medicine
D-dimer testing must be interpreted in the context of pretest probability [1C]. D-dimer testing alone is not
Marc J Moote, MS, PA-C
adequately sensitive or specific to diagnose or exclude PE [IIIC]. (See Figure 1.)
Surgery
Diagnostic testing determined by clinical likelihood estimation. The diagnostic approach differs depending on
David M Williams, MD
prior probability (see Figure 1, Tables 5, 6, 7, 8, and Appendix A. Low probability patients with negative DRadiology
dimer require no further testing [IA]. Others should generally undergo CT scanning [IA]. High or intermediate
Thomas W Wakefield,
probability
patients with negative CT or low probability patients with CT positive for sub- or segmental PE
MD
Vascular Surgery
require further investigation (see text) [IA].
Treatment
Initial Release
Heparin
June, 1998
Low molecular weight heparin (LMWH). LMWH is preferred for initial treatment over unfractionated heparin
Most Recent Major Update
(UFH) or fondaparinux due to better safety and outcomes [IA].
May, 2014
Outpatient use of LMWH for DVT. LMWH is appropriate for most patients with DVT to use at home [IIA].
Interim/Minor Revision
October, 2014
Some require initial brief hospital admission and stabilization. Clinically stable patients not at elevated risk due
to comorbidities can be managed entirely as outpatients using LMWH.
Ambulatory Care
Unfractionated heparin. UFH is no longer first line therapy. If UFH is used, it should be initiated and dosed in
Guidelines Oversight
a structured manner (see Appendix B) [IIA].
Grant M Greenberg, MD,
Minimum
time period. When warfarin is chosen as an oral agent, continue heparin (LMWH or UFH) until
MA, MHSA
either INR is optimally > 2.0 or for at least five days to minimize risk of extension of thrombosis or
R Van Harrison, PhD
occurrence/recurrence of embolism [IB].
Literature search service
If heparin contraindicated. When heparin is contraindicated (bleeding risk or drug sensitivity), consider a nonTaubman Medical Library
heparin anticoagulant agent (e.g., argatroban) [IIB]. If anticoagulation is contraindicated, place inferior vena
cava
filter to prevent pulmonary embolization [IIB].
For more information call:
734- 936-9771
Vitamin K antagonist: warfarin. Patients should begin warfarin on day 1 of heparin, and INRs should
optimally be > 2.0 before discontinuation of heparin [IA, B]. Start warfarin at the anticipated therapeutic dose [IC].
If warfarin contraindicated. Patients who can receive heparin but cannot take warfarin (e.g., during pregnancy)
Regents of the
may be anticoagulated with full-dose subcutaneous heparin [IA], preferably LMWH.
University of Michigan
Direct factor Xa inhibitors: rivaroxaban, apixaban. For selected patients (see text) begin rivaroxaban or
apixaban as immediate monotherapy. See Table 12 [IB].
These guidelines should not
Aggressive therapy. Patients with massive proximal DVT producing severe limb swelling and pain, or
be construed as including all
proper methods of care or
patients with massive PE producing shock or systemic hypoperfusion, may be candidates for emergent
excluding other acceptable
thrombolytic therapy or (in the case of DVT) thrombectomy. Such patients should be discussed with a
methods of care reasonably
directed to obtaining the same
consultant immediately [IID].
results. The ultimate
Duration
of therapy. Most patients with VTE should be anticogulated for 3 months [IB].
judgment regarding any
Team Leader
Grant M Greenberg, MD,
MA, MHSA
Family Medicine
* Strength of recommendation:
I= generally should be performed; II = may be reasonable to perform; III = generally should not be performed.
Levels of evidence for the most significant recommendations
A = randomized controlled trials; B=controlled trials, no randomization; C=observational studies; D=opinion of expert panel
APS
ABGs
BNP
CVA
Cerebrovascular accident
CTEPH
CTA
CTV
COCs
DVT
GSV
HIT
Heparin-induced thrombocytopenia
HRT
LMWH
MRA
MRV
NPV
NSAIDs
PE
PESI
PERC
PE Rule-out Criteria
PPV
PTS
Post-thrombotic syndrome
PT
Prothrombin time
RV
Right ventricle
VTE
Venous thromboembolism
V/Q scan
UFH
Table 3. Wells Criteria for Likelihood Estimation of Lower Extremity Deep Venous Thrombosis
Clinical Characteristic
Score
Active cancer (patient receiving treatment for cancer within the previous 6 months or currently receiving
palliative treatment)
Paralysis, paresis, or recent plaster immobilization of the lower extremities
Recently bedridden for 3 days or more, or major surgery within the previous 12 weeks requiring general
or regional anesthesia
Localized tenderness along the distribution of the deep venous system
Entire leg swollen
Calf swelling at least 3 cm larger than that on the asymptomatic side (measured 10 cm below tibial
tuberosity)
Pitting edema confined to the symptomatic leg
Previously documented deep-vein thrombosis
Collateral non varicose superficial veins
Alternative diagnosis at least as likely as deep-vein thrombosis
1
1
1
1
1
1
1
1
1
-2
Signs
Dyspnea
Chest pain (pleuritic)
Hemoptysis
Syncope
Apprehension
Cough
Diaphoresis
Tachypnea
Tachycardia
Evidence of lower extremity DVT
Hypotension
Fever
Crackles
Loud P2
Gallop rhythm
Chest X-ray b
Electro-cardiogram c
Sinus tachycardia
S1Q3T3
Rightward QRS axis
Transient RBBB
T wave inversion, ST segment depression
in right precordial leads
P pulmonale pattern
ST segment elevation in lead III
Hypoxia
Hypocapnia
Increased A-a gradient
Within each category findings are listed in approximate order of positive predictive value (expert opinion).
Most common finding is normal chest x-ray.
c
Changes found in fewer than 10% of cases of PE.
d
Cannot use normal ABGs to exclude PE. In one study, for patients with suspected PE and with normal paO2, paCO2, and P (A-a)O2, 38%
were found to have PE.
b
Points
3.0
3.0
1.5
1.5
1.5
1.0
1.0
Mean
Probability
3.6
20.5
66.7
Risk
Low
Intermediate
High
High-sensitivity Ddimer
Pulmonary angiography
96
96
60
82
92
90
89
92
58
57
97
68
25
96
97
Role in Diagnosis
Scan Report
Primary imaging study for
patients without
contraindication with
intermediate or high prior
probability or positive Ddimer
Establish diagnosis in highlikelihood patient with
symptoms and signs of PE
without need for CT, V/Q
scan, or angiography
Exclude PE in low-priorprobability patients (Wells
criteria)
Other tests
V/Q Scan
Commonly used
Color duplex
Doppler ultrasound
of lower extremity
Predictive
Values, %
Helical CT scanning
Study
Incidence
of PE
Overall performance
Normal scan
Low probability scan
Intermediate probability scan
High probability scan
<<1%
14%
30%
90%
<<1%
4%
16%
80%
<1%
14%
66%
>90%
Prior Probability
Estimation
(See Table 4)
Low Probability
D-dimer
Negative
Nega
tive
Intermediate Probability
High Probability *
Positive
for DVT
Optional:
Color duplex
Doppler venous
ultrasound
Positive
Positive for
segmental
or subsegmental
artery
No PE
Treatment
Negative
Negative
Positive
Discordant
Results***
Discordant
Results***
Positive for main
or lobar artery, or
positive
venous study
Treat for
PE
Positive
* Absent contraindication, begin full-dose LMWH immediately pending completion of diagnostic testing
** Venous study may be either color duplex Doppler venous ultrasound or CT venography.
***Discordance between prior probability and CTA findings requires further investigation, e.g., a second expert reading of the
CTA images, V/Q scanning, pulmonary angiography, or expert consultation.
Table 10. Pulmonary Embolism Severity Index (PESI) to Guide Emergency Department Disposition
PESI Score Interpretation
Criteria
Points
Age
Male gender
Hypotension (systolic blood
pressure <100 mmHg)
Tachycardia (pulse 100
beats/minute)
Tachypnea (respiratory rate 30
breaths/minute)
Hypoxia (oxygen saturation <90%)
Abnormal temperature
(temperature <36C)
Abnormal mental status
Chronic lung disease
Malignancy
Heart failure
+10 points
+30 points
+20 points
+20 points
+20 points
+20 points
Total point
score
Class I (none) *
Class II (1 percent) *
Class III (3.1 percent)
Class IV (10.4 percent)
Class V (24.4 percent)
65 or less
66-85
86-105
106-125
Greater
than 125
+60 points
+10 points
+30 points
+10 points
Ref: Aujesky D, Obrosky DS, Stone RA, Auble TE, Perrier A, Cornuz J, Roy PM, Fine MJ. Derivation and validation of a
prognostic model for pulmonary embolism. Am J Respir Crit Care Med. 2005;172(8):1041.
6
Recommendation
Adopted from Bauer KA, Duration of anticoagulation: applying the guidelines and beyond. Hematology Am Soc Hematol Educ Program.
2010;1:210-15; Kearon C et al, Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Am Coll of Chest Physicians. 2012 Feb;141(2
Suppl):e419s-494s; and Bates SM et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention
of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Am Coll of Chest Physicians.
2012 Feb;141(2 Suppl):e691s-736s.
Note: These general guidelines are based upon clinical trials and expert opinion. Each patient must be managed individually, which may
require an alternative treatment plan to that suggested above. Subspecialty consultation (i.e. hematology or pulmonology) for those with risk
factors or unprovoked DVT/PE is recommended as prolonged anticoagulation can be a complex decision.
a Thrombophilic risk factors include factor V Leiden; prothrombin gene mutation; hyperhomocysteinemia; congenital deficiencies of protein
C, protein S, antithrombin; and antiphospholipid antibodies.
Cost: Generic /
Brand
Monitoring
Consideration for
concurrent use with
UFH/LMWH during
Initiation
Warfarin /
Coumadin
5mg/10mg
$6 / $53-74
PT/INR prior to
initiation and then first
test 3 days after.
Subsequent monitoring
based on guidelines
(see Appendix C)
Rivaroxaban /
Xarelto
$NA / $287
None available or
needed
Not needed
$NA / $286-573
None available or
needed
Not needed
$NA / $315
None available or
needed
Apixaban /
Eliquis
Dabigatran /
Pradaxa
* Consider consultation when evaluating need for bridging with IV or Sub Q anticoagulation
Cost =For brand drugs, Average Wholesale Price minus 10%. AWP from Red Book Online 1/15/14. For generic drugs,
Maximum Allowable Cost plus $3 from BCBS of Michigan MAC List, 1/1/14. Prices calculated for 30 day supply unless
otherwise noted
Table 13. Indications for IVC Filter Placement
Contraindications to anticoagulation
Fresh surgical wound
Active GI or other bleeding (not occult blood)
Recent hemorrhage CVA
Multiple/major trauma
Recent neurosurgery
Inability or unwillingness to comply with oral anticoagulation
Pregnancy and impending delivery date
Complications of anticoagulation
Major bleeding
Heparin-induced thrombocytopenia *
Warfarin-induced skin necrosis
Failure of anticoagulation
Pulmonary embolectomy
*Agatroban is primary treatment; IVC filters may rarely be used in addition.
Clinical Background
Clinical Problem
ultrasonography.
The usefulness of duplex imaging
depends to some degree on the pretest probability of the
patient for a DVT.
Warfarin alone is inadequate. A study testing an oralagent-only approach (using acenocoumarol) was terminated
early due to an absolute risk excess for asymptomatic
pulmonary embolism of 13 per 100 patients. No reduction
in incidence of bleeding complications occurred with the
acenocoumarol-only strategy.
Preference for LMWH. LMWH is at least as effective
and safe as UFH, and in practical terms is clearly superior
because therapeutic dosing is more rapidly and dependably
achieved. A number of high-quality randomized controlled
trials have compared the several preparations of LMWH to
UFH in the treatment of DVT. As summarized in AHRQ's
evidence report, LMWH for venous thrombosis confers a
lower risk of major bleeding complication (absolute risk
reduction approximately 2 per 100 patients treated; relative
risk 0.6-0.7), a lower risk of recurrent thromboembolic
disease (RR 0.7-0.8), and a lower risk of death (RR 0.70.8).
UFH may still be elected in the case of renal disease with
GFR < 30 ml/min or clinically unstable patients who may
require surgery on an unpredictable basis, as LMWH is
only partially reversible by protamine. Use of UFH is
detailed in Appendix B.
Dosing of LMWH. Several LMWHs are currently
marketed. Each is dosed differently; some are administered
IV or SQ, and some SQ only. The common factor is that
doses are fixed in total amount or by body weight, not
adjusted by APTT.
The two most commonly used LMWHs are enoxaparin and
dalteparin. The package insert for enoxaparin (Lovenox)
calls for 1 mg/kg SQ q12hr or 1.5 mg/kg q24hr for VTE.
For obese and morbidly obese patients who weigh over 200
kg, consider consultation with a pharmacologist for dosing
that potentially exceeds 400 mg daily. Our opinion is that
once daily dosing is superior due to improved patient
compliance for non-pregnant patients. Twice daily dosing
should be used in pregnancy due to increased GFR after 20
weeks, but once daily dosing may still be considered to
enhance compliance. Dalteparin is used 120 anti-Xa
units/kg SQ q12hr to treat VTE.
Optimal duration of heparin therapy. For UFH, a five
day course has been shown to be as effective as longer
courses of treatment in preventing recurrent thrombosis,
provided that warfarin is started early (usually within 24
hours of diagnosis) and therapeutic oral anticoagulation is
achieved prior to discontinuing heparin. LMWH has not
been specifically tested but is believed to behave similarly.
Certain patients may use LMWH as the sole antithrombotic
agent throughout their course.
For patients with
malignancies and acute DVT, that strategy appears to
roughly halve the risk of recurrence without an increase in
adverse events and avoids difficult warfarin management
resulting from variable food intake. For asymptomatic
patients with DVT limited to the calf and no risk factors,
serial ultrasound imaging is preferred over anticoagulation.
14
15
17
Disclosures
The University of Michigan Health System endorses the
Guidelines of the Association of American Medical
Colleges and the Standards of the Accreditation Council for
Continuing Medical Education that the individuals who
present educational activities disclose significant
relationships with commercial companies whose products
or services are discussed. Disclosure of a relationship is not
intended to suggest bias in the information presented, but is
made to provide readers with information that might be of
potential importance to their evaluation of the information.
Team Member
Brian Brophy, MD
Krik Frey, MD, PhD
Relationship
None
Consultant
Grant
Stock
James Froelich, MD
Consultant
Company
MIM Software,
Lilly,
AVID
Radiopharmaceuticals,
BayerSchering,
Siemens and
Piramal
Imaging
GE Healthcare
General Electric,
Novo-Nordisk,
Bristol-MyersSquibb, Merck,
Medtronic
Pfizer, Merck,
Janssen,
BoehringerIngelheim,
Sanofi-Aventis
None
None
None
None
None
Consultant
Selected References
Bates SM et al. VTE, thrombophilia, antithrombotic
therapy, and pregnancy: antithrombotic therapy and
prevention of thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice
Guidelines. Am Coll of Chest Physicians. 2012 Feb;141(2
Suppl):e691s-736s.
Bates SM, Jaeschke R, Stevens SM, Goodacre S, et al.
Diagnosis of DVT: antithrombotic therapy and prevention
of thrombosis, 9th ed: American College of Chest
Physicians Evidence-based Clinical Practice Guidelines.
Chest, 2012; 141(2 Suppl):e351S-418S.
Bauer KA, Duration of anticoagulation: applying the
guidelines and beyond. Hematology Am Soc Hematol Educ
Program. 2010;1:210-15.
Boston
Scientific, Cook
Acknowledgements
The following individuals are acknowledged for their
contributions to previous versions of this guideline.
1998: Lee A. Green, MD, MPH, William P. Fay, MD, R.
Van Harrison, PhD., Mary D. Kleaveland, MD, Richard L.
Wahl, MD, Thomas W. Wakefield, MD, John G. Weg,
MD, David M. Williams, MD.
2004: Lee A. Green, MD, MPH, William P. Fay, MD,
Kirk A. Frey, MD, PhD, R. Van Harrison, PhD, Mary D.
23
Available at:
http://www.clevelandclinicmeded.com/medicalpubs/disease
management/hematology-oncology/hypercoagulable-states/
Kahn SR, Shapiro S, Wells PS, et al; for the SOX Trial
Investigators. Compression stockings to prevent postthrombotic syndrome: a randomized placebo-controlled
trial. Lancet. 2013.
Kearon C, Akl EA, Comerota AJ et al. Antithombotic
therapy for VTE disease: antithrombotic therapy and
prevention of thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest, 2009; 141:e419s-e494s/
Kline JA, et al. Clinical criteria to prevent unnecessary
diagnostic testing in emergency department patients with
suspected pulmonary embolism. J Thromb Haemost 2004;
2: 124755.
Kline JA, et al. Prospective multicenter evaluation of the
pulmonary embolism rule-out criteria. J Thromb Haemost
2008; 6: 77280.
Klok FA, Kruisman E, Spaan J, Nijkeuter M, Righini M,
Aujesky D, Roy PM, Perrier A, Le Gal G, Huisman MV.
Comparison of the revised Geneva score with the Wells
rule for assessing clinical probability of pulmonary
embolism. J Thromb Haemost. 2008 Jan;6(1):40-4. Epub
2007 Oct 29.
Harenberg J. Development of
idrabiotaparinux for anticoagulant
Haemostasis. 2009; 102: 811-815.
idraparinux and
therapy. Thromb
24
Appendix A
Diagnostic Stratification Scoring Tools for DVT and PE
Multiple validated scoring tools have been developed to facilitate both diagnosis and management options.
Presented below are some tools not specifically discussed in the text of the guideline, but are known to be clinically
useful.
The Revised Geneva Score can be applied to determine pre-test probability for VTE diagnosis.
The Wells DVT Criteria, as with the Geneva score, can be applied to determine pre-test probability specific
to DVT (not PE). (The modified Wells Criteria, Table 5 is specific to PE.)
The PERC criterion is a decision tool to minimize need for diagnostic testing for PE for patients meeting the
criteria.
Regression
Coefficients
Points
0.39
1.05
1
3
0.78
0.45
0.97
0.74
3
2
1.20
0.67
1.34
3
5
4
Risk Factors
Age > 65 y
Previous DVT or PE *
Surgery (under general anesthesia) or fracture (of the lower limbs within 1 month)
Active malignant condition (solid or hematologic malignant condition, currently
active or considered cured < 1 year)
Symptoms
Unilateral lower-limb pain
Hemoptysis
Clinical Signs
Heart rate
75-94 beats/minute
> 95 beats/minute
Pain on lower-limb deep venous palpation and unilateral edema
Clinical probability
Low
Intermediate
High
0-3 total
4-10 total
> 11 total
26
Appendix B
Use of Unfractionated Heparin (UFH)
Weight-Adjusted Heparin
Nomogram
Dosing UFH. Careful monitoring of UFH therapy must be performed at regular intervals to ensure that this agent is
effective and safe; see Monitoring Therapy below. Six hours after initiation of standard heparin therapy for VTE
approximately 1/3 of patients will have a sub-therapeutic aPTT, 1/3 will have an aPTT within the therapeutic range,
and 1/3 will have a supratherapeutic aPTT. Failure to achieve a therapeutic aPTT is associated with a marked
increase in recurrent thrombotic events. If heparin is administered in adequate amounts to patients with DVT,
symptomatic PE will occur in only 5% of patients, and fatal PE will occur in < 0.5%. Combined analysis of 7
studies in which patients with VTE received a 5000 U bolus of heparin and a continuous infusion of 30,000-40,000
U/24 hour indicates that the risk of recurrent thrombosis is 5.7%.
Route of administration. Full dose UFH can be administered either by continuous intravenous (IV) infusion or by
intermittent subcutaneous (SQ) injection. However, analyses of multiple randomized trials suggest that SQ UFH is
as effective as IV UFH in the treatment of DVT, provided that an initial IV bolus dose (5-10,000 U) is given, large
doses of heparin are administered (usually > 17,500 U SQ BID), and heparin therapy is monitored closely.
UFH can be administered as continuous IV infusion, intermittent IV boluses, or SQ boluses. Continuous infusion is
more readily monitored and adjusted, and probably achieves therapeutic levels more rapidly; hence it is the standard
in our institution. There is only a single small study of patient preferences, which found that most patients preferred
SQ administration, but IV equipment was not portable in that study.
The effectiveness of UFH therapy is usually monitored by the activated partial thromboplastin time (aPTT). The
aPTT is readily available and relatively inexpensive. Several studies have shown that anticoagulation guided by
nomograms is superior to individual physician-guided therapy, which varies significantly. Published nomograms
have been based on the aPTT which can be used in place of anti-Xa above, but have been shown to have a higher
error rate, require more frequent blood draws, and may result in an increased time to therapeutic anticoagulation.
Monitoring therapy. An aPTT time of 50 to 83 seconds is generally considered therapeutic. In patients whose
baseline aPTT is prolonged (e.g. due to lupus-type inhibitor), anti-factor Xa should be considered instead of aPTT for
monitoring heparin therapy. The aPTT or anti-FXa is usually measured every 6 hours until stable anticoagulation is
achieved, then each morning. In patients receiving SQ heparin every 12 hours, clotting times are measured 6 hours
after injection. Platelet count monitoring for HIT for UHF therapy should be carried out as for LMWH.
27
Appendix C
28
APPENDIX D
Algorithm For Use Of V/Q Scan In PE Diagnosis
29