January 30,

2017 DVT AND PE ANTICOAGULATION MANAGEMENT RECOMMENDATIONS

Introduction:

Over the past six decades, warfarin has proven effective in reducing the risk of recurrent venous
thromboembolism (VTE) in patients with acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE).
However, there have been multiple challenges with using warfarin including delayed onset of action, need for
bridging and monitoring as well as many drug-drug and drug-food interactions. Hence, long years of research
have led to the development of direct oral anticoagulants (DOACs). Of the four currently FDA-approved DOACs,
one is a direct thrombin inhibitor (dabigatran) and the other three are direct factor Xa inhibitors (apixaban,
edoxaban and rivaroxaban). DOACs have been found to be at least as effective as warfarin with fewer bleeding
complications. This document provides evidence based recommendations for the anticoagulation management of
VTE.

Evidence:

DOACs provide more convenient treatment of VTE in the outpatient setting compared to heparin + warfarin due
to less monitoring, and drug-drug and drug-food interactions. The 2016 CHEST guidelines suggest treatment of
DVT of the leg and PE, in the absence of cancer, with a DOAC over warfarin therapy (Grade 2B) based on the
potential for less bleeding and greater convenience with similar efficacy.1 Dabigatran and edoxaban require 5-10
days of parenteral anticoagulation prior to their use whereas rivaroxaban and apixaban can be started immediately
for the management of acute VTE. The clinical trials with rivaroxaban and apixaban demonstrated similar
efficacy outcomes compared to heparin + warfarin with less major bleeding.2,3,4 Insurance coverage of the
DOACs is variable but improving. There are manufacturer provided copay discounts available for patients with
private insurance but not for those with state funded insurance. Most patients, regardless of insurance status, are
able to get 1 month of medication free of charge through manufacturer provided discount cards. Patient selection
is important to maximize efficacy, safety, and compliance with therapy. Exclusion criteria based on criteria used
in the clinical trials and other theoretical contraindications are necessary to assess candidacy for DOAC treatment
(Table 1, see appendix). Warfarin might be considered in case of severe allergies to the DOACs or in patients
with end stage renal disease (ESRD).

The 2016 CHEST Guidelines for Antithrombotic Therapy for VTE Disease support home treatment of low-risk
PE (Grade 2B) and DVT (Grade 1B) in clinically stable patients with good cardiopulmonary reserve, good social
support with ready access to medical care, and who are expected to be compliant with follow-up.1 For PE, the
CHEST guidelines support the use of the PE severity index (PESI) to identify patients with a low mortality risk
(~1% at 30 days) who may be suitable for home management acknowledging that the risk score is only one of
many considerations when determining the need for hospital admission after PE (Table 2, see appendix).1,5,6 The
PESI has been simplified (Table 2, see appendix) for usability with retention of its prognostic accuracy.7 A score
of 0 (i.e. the patient has no variables of the score) is deemed low risk. Please refer to “Massive and Submassive
Pulmonary Embolism Algorithm” document for further recommendations regarding thrombolytic therapy in
patients with PE.

1
Minneapolis Heart Institute
Anticoagulation and Thrombophilia Clinic
Tel: 612-863-6800
 January 30,
2017 DVT AND PE ANTICOAGULATION MANAGEMENT RECOMMENDATIONS

Recommendations:

1- We suggest using a DOAC over heparin/warfarin for the management of lower or upper extremity DVT
and or PE not associated with cancer.
2- We particularly suggest using apixaban or rivaroxaban without parenteral anticoagulation, to help simplify
transitions of care. Consider out of pocket cost.
3- We suggest using low molecular weight heparin (LMWH) over warfarin or DOACs in cancer associated
lower extremity DVT and or PE. May consider a DOAC as off label choice in case of allergy or intolerance
to LMWH.
4- Warfarin might be considered in case of severe allergy to DOACs or in case of ESRD.
5- In patients with lower or upper extremity DVT and or PE who receive extended therapy, we suggest that
there is no need to change the choice of anticoagulant after the first 3 months.
6- Suggest treatment at home or early discharge over standard discharge in low-risk patients with adequate
home circumstances:
A. Clinically stable with good cardiopulmonary reserve
B. No recent bleeding, severe renal or liver disease, or severe thrombocytopenia (i.e., <70,000/mm3)
C. Expected to be compliant with treatment and
D. Patient feels well enough to be treated at home
7- Consider using the simplified PESI (Table 2) to help identify low risk patients with PE who may be eligible
for outpatient treatment. This should not replace clinical judgement.
8- In patients with acute proximal DVT of the leg, we suggest anticoagulation therapy alone over catheter
directed thrombolysis (CDT).
9- Consider CDT in patients with severe lower extremity DVT (e.g., phlegmasia), high risk of post-
thrombotic syndrome, and low risk of bleeding.
10- In patients with acute upper extremity DVT involving the axillary or more proximal veins, we suggest
anticoagulation therapy alone over thrombolysis.
11- Consider using CDT for severe upper extremity DVT with high risk for post-thrombotic syndrome and
low risk for bleeding, especially in cases with underlying thoracic outlet syndrome (TOS). First rib
resection can follow CDT in patients with TOS.
12- In catheter-induced upper extremity DVT involving the axillary or more proximal veins, we suggest
anticoagulation therapy. We favor anticoagulation for up to three months if the thrombosis is symptomatic,
associated with cancer, or the catheter remains in place. A longer duration of anticoagulation may be
warranted if the catheter remains in place, particularly for patients with cancer. It is reasonable to continue
using the catheter as long as it is functional. If the catheter is not functioning, the catheter can be removed
as long as the patient is on therapeutic anticoagulation.
13- We recommend against the use IVC filter in patients with acute DVT or PE who are treated with
anticoagulants.
14- We recommend three months of anticoagulation for provoked proximal DVT and or PE.
15- In patients with unprovoked VTE, we suggest (for first event) or recommend (for recurrent event)
extended anticoagulation therapy over three months period in patients with low or moderate bleeding risk.
We recommend (for first event) or suggest (recurrent event) three months of anticoagulation in patients
with high risk of bleeding.
16- In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be
reassessed at periodic intervals (e.g., annually).

2
Minneapolis Heart Institute
Anticoagulation and Thrombophilia Clinic
Tel: 612-863-6800
 January 30,
2017 DVT AND PE ANTICOAGULATION MANAGEMENT RECOMMENDATIONS

17- We suggest aspirin over no aspirin in patients with unprovoked proximal DVT or PE who are stopping
anticoagulation therapy and have no contraindication to aspirin.
18- In Patients with isolated sub-segmental PE without proximal DVT, we suggest clinical surveillance over
anticoagulation in patients with low, and suggest anticoagulation over surveillance in patients with high,
risk for VTE recurrence.
19- In high risk symptomatic patients with provoked or unprovoked distal (below the popliteal vein) DVT, we
recommend three months of anticoagulation over shorter or longer periods. Asymptomatic lower risk
patients with high risk of bleeding can be followed by ultrasound periodically (e.g., every 2 weeks).
20- In patients with acute DVT of the leg, we suggest not using compression stockings routinely to prevent
PTS. However, we recommend using them in patients with symptomatic edema.
21- Please refer to “Massive and Submassive Pulmonary Embolism Algorithm” document for further
recommendations regarding thrombolytic therapy in patients with PE.
22- Please refer to the DOAC related protocols for dosing, management of bleeding and peri-procedural
anticoagulation recommendations.
23- Please refer to the warfarin and heparin protocols for dosing and monitoring.

References

1. Kearon C, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report.
Chest. 2016 Feb;149(2):315-52.
2. Büller HR, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med.
2012 Apr 5;366(14):1287-97.
3. EINSTEIN Investigators, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J
Med. 2010 Dec 23;363(26):2499-510.
4. Agnelli, G et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013
Aug 29;369(9):799-808.
5. Aujesky D, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir
Crit Care Med. 2005 Oct 15;172(8):1041-6.
6. Jiménez, D et al. Prognostic models for selecting patients with acute pulmonary embolism for initial
outpatient therapy. Chest. 2007 Jul;132(1):24-30.
7. Jiménez, D et al. Simplification of the pulmonary embolism severity index for prognostication in patients
with acute symptomatic pulmonary embolism. Arch Intern Med. 2010 Aug 9;170(15):1383-9.

3
Minneapolis Heart Institute
Anticoagulation and Thrombophilia Clinic
Tel: 612-863-6800
 January 30,
2017 DVT AND PE ANTICOAGULATION MANAGEMENT RECOMMENDATIONS

APPENDIX

Table 1: Proposed Exclusion Criteria for the use of a DOAC#

Patient History Lab Values/Vitals Medications Social History

Active cancer Hgb < 10 g/dL Dual Antiplatelet No prescription
treatment with evidence of Therapy insurance coverage
bleeding
Mechanical Heart Platelets < 70 K
Major Drug Homeless
Valve Interactions with
Concern for active CrCl < 30ml/min Rivaroxaban/ Known history of
bleeding for rivaroxaban* Apixaban (Strong poor compliance
CrCl < 25ml/min dual inducers of P-gp with medications
for apixaban* and CYP3A4 eg, and/or follow up
Bleeding risk ALT >3 times ULN rifampin, phenytoin, EtOH or IV drug
outweighs risk of or carbamazepine, St. abuse
thromboembolic event T Bili >1.5 time John’s wort)
ULN

Bacterial endocarditis Blood Pressure Major Drug

>180/110 mmHg Interactions with
Rivaroxaban
(strong dual
inhibitors of P-gp
and CYP3A4 eg,
ketoconazole,
itraconazole,
ritonavir,
clarithromycin)
HIT ≤ 3 months Severe allergy to the
DOAC*
Pulmonary arterial
hypertension
Child-Pugh Class B/C
Cirrhosis or elevated
INR related to liver
disease
Pregnancy

*Warfarin might be considered in case of severe allergies to the DOACs or in case of end stage renal disease
(ESRD).
CrCl: creatinine clearance, DOAC: direct oral anticoagulant, EtOH: ethanol, Hgb: hemoglobin, HIT: heparin
induced thrombocytopenia ULN: upper limit of normal, P-gp: permeability glycoprotein.
4
Minneapolis Heart Institute
Anticoagulation and Thrombophilia Clinic
Tel: 612-863-6800
 January 30,
2017 DVT AND PE ANTICOAGULATION MANAGEMENT RECOMMENDATIONS

Table 2: Original and Simplified PESI Score 5,6,7

5
Minneapolis Heart Institute
Anticoagulation and Thrombophilia Clinic
Tel: 612-863-6800
 January 30,
2017 DVT AND PE ANTICOAGULATION MANAGEMENT RECOMMENDATIONS

Figure 1: Anticoagulation Therapy Algorithm for VTE

Proximal Isolated Distal DVT Cancer- Upper

DVT or PE associated extremity DVT
provoked or unprovoked

Provoked Mild Severe Extended

Unprovoked -Anticoagulation*
symptoms or symptoms or anticoagulation¶
high bleeding risk for -Consider CDT
risk extension then 1sr rib
Anticoagul resection in TOS
Low to High
ation for 3
months* moderate bleeding
bleeding risk Anticoagulation
Serial
risk for 3 months*
imaging x2
weeks
Anticoagul
Extended ation for 3
anticoagulati months*
on* Propagating
thrombus

Anticoagulation
for 3 months*

CDT: catheter directed thrombolysis, DOAC: direct oral anticoagulant, DVT: deep vein thrombosis, LMWH:
low molecular weight heparin, PE: pulmonary embolism, TOS: thoracic outlet syndrome.

* We favor using a DOAC over enoxaparin + warfarin.

¶ We favor low molecular weight heparin over a DOAC or warfarin.

6
Minneapolis Heart Institute
Anticoagulation and Thrombophilia Clinic
Tel: 612-863-6800