Dilemmas in Venous

Thromboembolic Disease 2013

Margaret M. Johnson, MD
Associate Professor of Medicine
Chair, Division of Pulmonary Medicine
Mayo Clinic Florida
Johnson.margaret2@mayo.edu

16 November 2013
Santiago, Chile
Outline
Role of new anticoagulant therapy in
thromboembolic disease
Prophylaxis & treatment
Clinical decisions
Duration of anticoagulation after an unprovoked VTE
Is aspirin indicated for secondary prevention ?
When should inferior vena cava filters be placed
Management upper extremity deep vein thrombosis


Prophylaxis and Treatment:2000
Prophylaxis
Heparin
Low
molecular
weight
heparin
Treatment
Heparin
IV
Subcutaneous
Low molecular
weight heparin
Warfarin /Vit K
antagonist
Alteplase


Prophylaxis and Treatment:2013
Prophylaxis
Heparin
Subcutaneous
Low molecular
weight heparin
Fondaparinux
Rivaroxaban
Apixaban
Dabigatran

Treatment


Heparin
IV
Subcutaneous
Low molecular
weight heparin
Warfarin /Vit K
antagonist
Fondaparinux
Rivoraxaban
Alteplase



New Anticoagulants For Venous
Thromboembolsim
Factor Xa inhibitor
Subcutaneous
Fondaparinux (Arixtra)
Oral
Rivaroxaban (Xarelto)
Apixiban (Eliquis)
Edoxaban
Direct thrombin inhibitor
Oral
Dabigatran (Pradaxa)



Fondaparinux Dosing
Prophylaxis: Fixed dose Treatment: Weight Based
Prophylaxis
2.5 mg/daily
Subcutaneously
Treatment
of DVT or
PE
5.0 mg/daily
Wt < 50 kg
7.5 mg/daily
Wt 50-100
kg
10 mg/daily
Wt> 100 kg
Summary of Fondaparinux
Approved for prophylaxis in patients undergoing hip,
knee and abdominal surgery
Fewer DVT following hip and knee surgery compared with
enoxaparin
Similar bleeding
Treatment of DVT and PE
PE therapy must begin in hospital
Noninferior
Compared with LMWH in DVT treatment
Compared with UFH in PE treatment
No comparison between fondaparinux & LMWH in PE treatment

Rivaroxaban (Xarelto)
Oral, once daily, Factor Xa inhibitor
Limited food/drug interactions
Approved (July 2011) for VTE prophylaxis in
orthopedic surgery after comparison with
enoxparin
Significant reduction in
All VTE
Major VTE
VTE + all cause mortality (RECORD 4)
Equivalent bleeding


Oral Rivaroxaban for Symptomatic DVT & PE


Acute DVT treatment: Rivaroxaban
NONINFERIOR
1
to enoxaparin + warfarin

36 events (2.1%) Rivaroxaban v. 51 events (3.0%)
enoxaparin + warfarin
HR 0.68 (CI 0.44 1.04), p < 0.001-noninferiority
Acute PE treatment (4,000 patients)
2
Rivoroxaban v. enoxaparin + warfarin
Similar number of recurrences
Less major bleeding with rivoroxaban

1
The EINSTEIN Investigators. N. Eng J Med 2010;363:2499
2
The EINSTEIN Investigators. N. Eng J Med 2012;366(14) 1287

Apixaban (Eliquis)
Oral direct factor Xa inhibitor
In 5395 patients with acute DVT or PE,
Apixiban was NONINFERIOR compared with
enoxaparin
Lower rate of major bleeding (RR 0.31, CI 0.17-
0.55)
Giancarlo A NEJM 2013;369:799-808
Not currently FDA approved for VTE in US
Orthopedics prophylaxis in Europe
Dabigatran (Pradaxa)
Oral direct thrombin inhibitor
Approved for DVT prophylaxis in orthopedic
surgery in Europe and Canada
RECOVER Study
2500 patients with acute PE
Dabigatran v. warfarin
Similar recurrence and major bleed
Total bleed lower with dabigatran
NEJM 2009
No approval in US for VTE prophylaxis or
treatment
Take Home Points: New Anticoagulants
Factor Xa inhibitors
Fondaparinux: (Arixtra)
Subcutaneous
Prophylaxis in orthopedic & abdominal surgery
Treatment of deep vein thrombosis and pulmonary embolism
Pulmonary embolism treatment must begin in hospital
Rivoroxaban (Xarelto)
Prophylaxis (orthopedic surgery)
Treatment in DVT and PE
Apixaban (Eliquis)
Supportive data for orthopedic prophylaxis and treatment; not
FDA approved
Direct thrombin inhibitors
Dabigatran (Pradxa)
No indication in US for VTE prophylaxis or treatment despite
similar efficacy in pulmonary embolism treatment



Duration of Anticoagulation
Unprovoked proximal deep vein thrombosis or
pulmonary embolism and low to moderate
risk of bleeding, extended anticoagulation
therapy is recommended
For those with high risk of bleeding, three
months of anticoagulation is recommended

ACCP 2012;141(2)
Duration of Anticoagulation
Unprovoked venous thromboembolism
associated with high rate of recurrence
Extended anticoagulation with warfarin
Risk of bleeding, costly, bothersome, drug
interactions
Clot Predicts Clot
Risk of Recurrence
474 patients followed for recurrence
13% recurrence after 5 yrs
Unprovoked clot greater risk for recurrence than
thrombophilia
Christiansen, SC. JAMA 293; 19: 2352. 2005
1626 patients after anticoagulation stopped
Unprovoked clot associated with 40 % recurrence
rate at 10 years
Odds ratio higher than with thrombophilia
Prandoni P. Haematologica 2007;92(2)199
Recurrence Risk
Patients presenting with pulmonary embolism
are more likely to have a subsequent
pulmonary embolism rather than deep vein
thrombosis
Males are at greater risk of recurrence after
unprovoked episode
Risk of recurrence is higher if initial
anticoagulation < 3 months
Recurrence is the same with 3 or 6 months of
therapy

Oral Rivaroxaban for VTE: Prolongation Trial

Rivaroxaban v. placebo
Superiority trial comparing additional 6-12 months
anticoagulation after 6-12 months anticoagulation
Prolonged therapy associated with lower
recurrence
Recurrent VTE
8 events (1.3%) v. 42 events (7.1%)
HR 0.18 (CI 0.09 0.39), p < 0.001)
Bleeding not significantly different
4 nonfatal bleeds with rivaroxaban (0.7%) v. none
The EINSTEIN Investigators. N. Eng J Med 2010;363:2499
Oral Apixiban for VTE: Prolongation Trial

2,482 patients who had completed 6-12
months of anticoagulation
Randomized to apixiban 2.5 mg, 5.0 mg or
placebo
Risk of recurrence 8.8% in placebo v. 1.7% in
apixiban group
Recurrence rate not different between two doses
No significant excess bleeding with apixiban
All cause mortality higher in placebo group
Giancarlo A. NEJM 2013:368:699-708
Is Aspirin the Answer?
Can Aspirin Effective in Secondary
Prevention ? (ASPIRE Trial)
822 patients with first unprovoked clot who
had completed anticoagulation
Randomized to aspirin (100 mg) or placebo
Recurrence of VTE less but not significantly so
(6.5% v. 4.8%, p=0.09)
Underpowered-Had planned for N= 3,000
Lower incidence of both composite outcome
of myocardial infarction, stroke or recurrent
clot (8.0% v. 5.2%)

Brighton TA. NEJM 367:21, 1979. 2013

WARFASA Trial
Similar design as ASPIRE trial
402 patients who had completed
anticoagulation randomized to aspirin or
placebo
Aspirin significantly reduced recurrence of
venous thromboembolism
6.6% v. 11.8%, HR 0.58, (CI 0.36-0.93)
No difference in major or minor bleeding or
mortality
Becattini C NEJM 2012;366:1959

Take Home Points
Risk of recurrent venous thromboembolism is
substantial
Extended duration of anticoagulation reduces
recurrences
Continuation of warfarin associated with
bleeding risk, monitoring, and drug interactions
Data supports reduced recurrence risk with
rivoroxaban and apixiban compared with
placebo
Aspirin appears to reduce risk of recurrence
Inferior Vena Cava Filters
Consensus
Use in acute venous thromboembolism when
anticoagulation is CONTRAINDICATED
Also, complication or failure of anticoagulation
Do not use routinely in DVT or PE when
anticoagulation is not contraindicated
Uncertain
Use as adjunctive therapy to anticoagulation or
thrombolytic therapy in massive PE
Prophylactic use in trauma


Adjunctive Therapy in Massive PE
108 patients with massive PE in International
Cooperative Pulmonary Embolism Registry
(ICOPER)
1
11 patients received an IVC filter
No recurrent clot in these
12% recurrence without filter
10/11 survived 90 days
Retrospective review
2
33/248 (13%) got IVC filter + anticoagulation
No in hospital deaths in those with filter
NOT significant difference


1
Kucher N Vasc Med 2005;
2
Jha VM Cardiovas Intervent Rad 2010;33(4)739
Prophylactic Use of Inferior Vena
Cava Filters in Trauma
Highest incidence of venous thromboembolism
among all hospital patients
Up to 10% DESPITE pharmacological prophylaxis
Filter placement may be associated with
increased risk of deep vein thrombosis in spinal
cord injury
Incidence of DVT 11/54 (20%) with filter v. 3/58 (5%)
Only 1/112 had pulmonary emobolism-also had filter
Gorman PH. J Trauma 2009 66: (3)707
Recommendations for Prophylaxis
in Trauma
Prophylaxis
Heparin or low molecular weight heparin
Use with sequential compression devices if
extremely high risk
ACCP recommends AGAINST prophylactic use in
trauma
ACCP 2012;141(2)
All Grade 2C recommendations
Weak recommendation
Low or very low quality of data


Inferior Vena Cava Filters Associated
with Increased DVT at 2 Years

Are removable filters the answer?
Maybe, but
Removable filters often arent removed
71/679 (10%) were removed or attempted to be
removed
Sarosiek S. JAMA Int Med 2013; 173(7) 513
17/72 (23%)were removed or attempted to be
removed
Gaspard SF. Am Surg 2009 75(5):426
PREPIC 1998 NEJM
Caveats: Inferior Vena Cava Filters
The presence of an IVC filter is not an
indication for anticoagulation
Ungraded recommendation ACCP
The chance of successful removal decreases
with increasing duration of a removable filter
Filters should be imaged prior to removal
If substantial clot is present weeks of
anticoagulation should be utilized before removal
Kaufman JA. J Vasc Interv Radiol 2006;17:449


Upper Extremity Clot
Upper extremity clot involving the axillary or
more proximal veins
Anticoagulate
3 months duration
Fondaparinux or low molecular weight heparin
recommended over unfractionated heparin
ACCP 2012;141(2)

Catheter Associated Upper
Extremity Clot
Dont remove the catheter IF
It is still required
Is functional
Anticoagulate * 3 months
Even if catheter is removed
Continue anticoagulation if catheter remains
ACCP 2012;141(2)

Take Home Points
Acute clot with contraindication to or
complication or failure of anticoagulation is the
only consensus indication for IVC filter
Data limited on use as adjunctive therapy in
massive clot
Not indicated for routine prophylaxis
Conflicting data on use in trauma patients
VERY limited data
Removable filters are not commonly removed
IVC filter alone is NOT an indication for
anticoagulation

Take Home Points
Anticoagulation for 3 months recommended
for upper extremity clot
For catheter associated upper extremity clot
Make decision regarding removal of line based on
need for line NOT presence of clot
Anticoagulation is recommended for 3 months
even if catheter is removed
Continue anticoagulation longer than 3 months if
catheter remains in place