OBJECTIVES

Treatment of Venous Thrombosis and

Pulmonary Embolism
Prevent death from PE
Prevent post-thrombotic syndrome
Prevent recurrent venous thromboembolism (VTE)
Achieve these objectives with minimal side effects
and inconvenience
Treatment of VTE
Anticoagulants
Thrombolytic therapy
Caval interruption
Surgical removal
Anticoagulants
Initial treatment with heparin is necessary.
Induction period with heparin therapy can be
reduced to 5 days.
Treatment following hospital discharge is necessary.
LMWH is a major advance.
Optimal therapeutic range with warfarin established.
Optimal duration of warfarin therapy still to be established.
New oral small-molecule direct thrombin inhibitor.*
* Does not have FDA approval for any indication.
Thrombolytic Therapy
Not often indicated in venous thrombosis
Useful in major PE
Possible new indication in PE
Caval Filter
A single randomized trial has defined advantages
and drawbacks of caval filters. The results indicate
that inferior venacaval filters:
a) Prevent recurrent PE in short term
b) Increase the risk of recurrent deep venous
thrombosis (DVT) in the long term
Surgery
Endarterectomy for chronic thromboembolic
pulmonary hypertension can be life saving.
Venous surgery is rarely indicated.
Venous stenting combined with catheter-directed
thrombolytic therapy is being used in some
centers to treat patients with iliofemoral venous
thrombosis and severe obstruction.
Anticoagulants
Heparin
Vitamin K antagonists (warfarin)
LMWH
Danaparoid*
Hirudin*
Pentasaccharide*
Oral small-molecule direct thrombin inhibitor*
*Danaparoid is not approved by the FDA for use in the treatment of thrombosis or HIT. Natural hirudin is not approved by the FDA for any
indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis associated with HIT. Pentasaccharide and the new oral
small-molecule direct thrombin inhibitor do not have FDA approval for any indication.
Oral: Multiple clinical trials Small molecule DTI

*
Injection: Phase 3 Pentasaccharide*
Injection Hirudin*

Injection Danaparoid*
Oral Warfarin
Injection LMWH
Injection
Heparin
*Danaparoid is not approved by the FDA for use in the treatment of thrombosis or HIT. Natural hirudin is not approved by the FDA for any
indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis associated with HIT. Pentasaccharide and the new oral
small-molecule direct thrombin inhibitor do not have FDA approval for any indication.

DTI=direct thrombin inhibitor

Anticoagulants
TF VII
IX
Xa
X
IXa
a
II Va
IIa
VIIIa
FIBRINOGEN
FIBRIN
Coagulation Cascade
TF VII
IX
Xa
X
IXa
a
II Va
IIa
VIIIa
FIBRINOGEN
FIBRIN
WARF
WARF
WARF
WARF
UFH, LMWH
UFH, LMWH
UFH, LMWH
Established Anticoagulants
TF VIIa
IX
Xa
X
IXa
II Va
IIa
VIIIa
FIBRINOGEN
FIBRIN
New Anticoagulants
PENTASAC*
HIRUDIN*
ORAL SMALL-
MOLECULE DTI

*

* Natural hirudin is not approved by the
FDA for any indication; recombinant
hirudin (lepirudin) is approved for the
treatment of thrombosis associated with
HIT. Pentasaccharide and the new oral
small-molecule direct thrombin inhibitor
do not have FDA approval for any
indication.


DTI=direct thrombin inhibitor

New Anticoagulants for Treatment of DVT
Hirudin* (recombinant; lepirudin) is effective for
treating thrombosis associated with HIT.
The new oral small-molecule direct thrombin
inhibitor* appears promising in multiple clinical
trials.
Pentasaccharide* has been evaluated in phase 2
studies and is being tested in phase 3 studies.

* Natural hirudin is not approved by the FDA for any indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis
associated with HIT.The new oral small-molecule direct thrombin inhibitor do not have FDA approval for any indication.

Initial treatment with heparin is necessary.
Induction period with heparin therapy can be
reduced to 5 days.
LMWH can replace heparin and is now treatment
of choice.
Continued treatment following hospital discharge
is necessary.
Optimal therapeutic range with warfarin is an INR
of 2.0 to 3.0.
Optimal duration of warfarin therapy still to
be established.
Established Anticoagulants
Initial Treatment With Heparin Necessary
in Treating Proximal Vein Thrombosis
Confirmed
Symptomatic
Recurrence
Positive
Negative
Total
Placebo and
Acenocoumarol
12
48
60
Heparin and
Acenocoumarol
4
56
60
Group Total
16
104
120
P = 0.058
Data from Brandjes et al, 1992
Confirmed Symptomatic Recurrence and/or
Venographic Evidence of Significant Extension
and/or New High-Probability V/Q Scan
Positive
Negative
Total
Placebo and
Acenocoumarol
28
25
53
Heparin and
Acenocoumarol
7
42
49
Group Total
35
67
102
P < 0.001
Data from Brandjes et al, 1992
Event
Induction Period With Heparin
Can Be Reduced to 5 Days
Recurrent VTE
During heparin
During warfarin
Total during
treatment
Short
(4 days)
3.6%
3.3%
6.9%
Long
(9.5 days)
4.7%
1.6%
6.3%
Short
(5 days)
0%
7.1%
7.1%
Long
(10 days)
0%
7.0%
7.0%
Gallus 1986 (266 pts) Hull 1990 (199 pts)
Treatment Following Hospital
Discharge Necessary
Author Recurrent
VTE (%)
Lagerstedt 0
29
VTE = venous thromboembolism; SC = subcutaneous
Initial Course
of Heparin
5 days
Long-Term
Treatment
Hull 0
47
14 days Warfarin
vs
SC heparin 5000
twice daily
Warfarin
vs
no treatment
Hull et al, 1979; Lagerstedt et al, 1985
LMWH: A Major Advance
Weight-adjusted subcutaneous dosing predictable
(Handeland et al,1990; Bratt et al, 1990)
Mechanism of more predictable dose response
(Young et al, 1993, 1994)
Less osteopenia than UFH (Shaughnessy et al, 1995; Monreal et al,
1994)
Less HIT than UFH (Warkentin et al, 1995)
Once-daily subcutaneous dosing effective in DVT (Hull et al, 1992)
Outpatient treatment effective and safe (Levine et al, 1996;
Koopman et al, 1996)
Treatment of PE effective and safe (Columbus Investigators, 1997;
Simonneau et al, 1997)
Meta-Analysis
LMWH vs Heparin for Treatment of DVT
Primary Studies:
Duroux, 1991
Hull, 1992
Prandoni, 1992
Lopaciuk, 1992
Levine, 1996
Koopman, 1996
Fiessinger, 1996
Luomanmaki, 1996
Columbus, 1997
All studies
(fixed-effect model)
Simonneau, 1993
Lindmarker, 1994
Gould et al, 1999
Recurrent Thromboembolism
(n=3566)
OR 0.85
(P=0.28)
0.01 0.1 1 10 100
Favors
LMWH
Favors
UFH
Odds Ratio (OR)
Efficacy and Safety of Two Trials Using
Outpatient LMWH
Study
Levine
Koopman
Treatment
UFH
UFH
LMWH
LMWH
Number
253
198
247
202
Recurrent
VTE
6.7%
8.6%
5.3%
6.9%
Major
Bleeding
1.2%
2.0%
2.0%
0.5%
Hospital
6.5
Days in
1.1
8.1
2.7
Levine et al, 1996; Koopman et al, 1996
A Comparison of LMWH (Tinzaparin)
With UFH for the Treatment of Acute PE
Outcome Event IV Heparin SC LMWH 175 U/kg QD
Simonneau et al, 1997
Days 18 3 4
14 (4.5%) 12 (3.9%)
Death
Days 190
Days 1 8 2 3
6 (1.9%) 5 (1.6%)
Recurrent TE
Days 190
Days 18 5 3
8 (2.6%) 6 (2.0%)
Major bleeding
Days 190
Days 18 9 (2.8%) 9 (3.0%)
22 (7.1%) 18 (5.9%)
Composite
Days 190
n = 308 n = 304
IV=intravenous; SC=subcutaneous; QD=once daily; TE=thrombotic events
Harrison et al, 1998
Treatment of DVT in Practice
Two hospitals, 1 year
113 consecutive patients referred to thrombosis units
13 excluded (no local treatment [5], outpatient UFH [8])
11 hospitalized
Comorbid disease (4)
High risk of bleeding (3)
Pain control (1)
Inadequate home support (1)
Weekend admission (2)
89 received outpatient LMWH
75% self-injected or had family member perform injections.
Harrison et al, 1998
Outcomes
Recurrent VTE 7% (6/89)
Fatal PE and bleed (1)
DVT (5); all had cancer

Major Bleeding 2% (2/89)
Fatal bleed and PE (1)
Arm bleed: hospitalized

Patient Satisfaction Very: 91% (75/82)
Dosing in obese patients and in renal
insufficiency
Dosing in pregnancy
Protamine reversal
Interchangeability of different preparations
LMWH: Outstanding Questions
Trial of Intensive versus Less Intensive
Warfarin Therapy (3 Months)
Regimen
INR 3.04.0
INR 2.03.0
Frequency of
Recurrent VTE
2%
2%
Frequency of
Bleeding
Complications
22%
4%
Hull et al, 1982
Warfarin
Study
No. of
Patients
%
Annualized
Recurrence
No. of
Patients
%
Annualized
Recurrence
Prandoni et al, 1996 145 19 105 4
BTS, 1992 596 13 116 3
Hirsh, 1995 117 15 70 1
Levine et al, 1995 212 16 89 0
Schulman et al, 1995 553 9 344 3.5
IDIOPATHIC DVT* POSTOP DVT
* Idiopathic and continuing risk factors
BTS = British Thoracic Society
Risk Factors for Recurrence
Study
Schulman et al, 1995
Rate of Recurrence After Discontinuing
Anticoagulants in Patients
With Idiopathic Thrombosis
Kearon et al, 1999
Months of
Observation
24
10
No. of
Patients
553
83
%
Annualized
Recurrence
9
27
Recurrent VTE
Major bleeding
Warfarin versus Placebo After Initial
3 Months of Warfarin Therapy for
First Idiopathic VTE
Placebo
(n=83)
17 (27%/patient-year)
0 (0%/patient-year)
Warfarin
(n=79)
1 (1.3%/patient-year)
3 (3.8%/patient-year)
Prespecified interim efficacy analysis led to termination after
an average of 10 months.
Kearon et al, 1999
Risk Factors for Recurrence in Patients
With Idiopathic VTE Treated With
Warfarin for 3 Months
All patients
Antiphospholipid
antibody
Factor V Leiden
Prothrombin
mutation
Hazard
Ratio
4.0
(1.213)
0.5
2.2
Kearon et al, 1999
No Recurrence
49/66 (74)
2/61 (3)
17/59 (29)
2/59 (3)
No./Total No. (%)
Recurrent VTE
17/66 (26)
4/16 (25)
3/16 (19)
1/16 (6)
No./Total No. (%)
Major and Fatal Bleeding During
Oral Anticoagulation
Finn et al, 1993
1% cumulative incidence of fatal bleeding at 1 year and 2% at 3 years
Palareti et al, 1996
1.1% major bleeds/100 patient-years
0.25% fatal bleeds/100 patient-years
Schulman et al, 1997
2.7% major hemorrhage in 6-month group compared with 8.6% in the
indefinite treatment group
Kearon et al, 1999
3.8% per patient-year incidence of major bleed in patients on therapy
for 3 months
Low Risk
Moderate Risk
High Risk
MI = myocardial infarction; DM = diabetes mellitus
Risk of Bleeding
Major Bleeding
2%
5%
23%
3%
12%
48%
3 Months 12 Months
(0)
(1 or 2)
(3 or 4)
Age 65 years
Stroke in past
Gastrointestinal bleeding in past
MI, anemia (Hct <30%), renal failure (Cr >1.5 mg/dL), or DM
Beyth et al, 1998
No. Risk Factors
Risk of Major Bleeding During Warfarin
Anticoagulation
< 65 years of age with no other risk factors: 3%
65 years of age with multiple risk factors: 42%


820 Patients Followed for 1 Year
Beyth et al, 1998
Fatality Rates With Recurrent VTE
and With Bleeding
5% to 7% of recurrent PE events are fatal
(Douketis et al, 1998).
20% of major bleeding events are fatal
(Schulman et al, 1997; Palareti et al, 1996).
Nonfatal recurrent VTE more serious than
nonfatal major bleeding.

Duration of Anticoagulation
VTE recurrences occur at a rate of 10%25% in the first year
anticoagulants are discontinued. (Schulman 1995, Kearon
1998)
Risk of recurrent VTE decreases over time, but risk of
bleeding increases.


8.6%

2.7%

Major
hemorrhage
2.6% 20.7% Rate of VTE
recurrence
Indefinite
Treatment

6 Months of
Therapy
Schulman 1997

Optimal Duration of Anticoagulant Therapy
for Symptomatic Venous Thrombosis:
Recommendations
Indication Duration
Proximal thrombosis: reversible cause
Idiopathic proximal vein thrombosis
Idiopathic calf-vein thrombosis
Calf-vein thrombosis: reversible cause
3 to 6 months
6 months to >1 year
6 months to 1 year
6 weeks to 3 months
Factors That May Influence Duration
of Oral Anticoagulation
Shorter Course
Bleeding risk
Unstable anticoagulant
response
Inconvenient
anticoagulation
Fear of recurrence or
bleeding
Longer Course
VTE presentation (eg,
massive PE)
Poor cardiopulmonary
reserve
Severe post-thrombotic
syndrome
Thrombophilia
Recurrent VTE
Potential Indications for Indefinite
Anticoagulant Therapy
Inherited thrombophilia: AT, protein C and S
deficiency not factor V Leiden or prothrombin
mutation
Antiphospholipid syndrome
Recurrent idiopathic VTE
Malignancy
Thromboembolic pulmonary hypertension
AT = antithrombin
Oral Small-Molecule
Direct Thrombin Inhibitor*
Direct comparison with warfarin currently
in progress
If oral small-molecule direct thrombin inhibitor is
as effective as warfarin, the advantages will be
as follows:
No monitoring
Fewer drug interactions
* The new oral small-molecule direct thrombin inhibitor does not have FDA approval for any indication.
Thrombolytic Therapy
DVT
Thrombolytic therapy achieves complete early lysis in
30% to 40% of cases (heparin 10%).
Increases bleeding threefold.
Probably reduces the incidence of post-thrombotic
syndrome. However, risk of severe post-thrombotic
syndrome about 10% with adequate anticoagulation.
Catheter-directed thrombolysis with administration into
thrombus claimed to be more effective, but further
study is required.
Thrombolytic Therapy
PE
Two-hour high-dose t-PA or urokinase effective.
Improves resolution at 24 hours but not at 7
days.
Role in massive embolism accepted.
Role in submassive, major embolism
controversial.
Thrombolysis
(n=188)
38%
Thrombolysis for DVT
45% 13%
No Change Marked Lysis
Major
Bleeding
Hirsh et al, 1996
Pooled analysis of eight randomized trials
Repeat Venography
Heparin
(n=144)
78% 10%
3.5%
Thrombolysis 12%
Thrombolysis for PE
30% 58%
2 hours 1 day 1 month
Dalen et al, 1997
Improvement of Perfusion
Heparin 0% 10% 60%
45%
1 week
40%
Accelerates resolution
No effect on extent of resolution
No effect on frequency of recurrence
Classification of Acute PE
Massive PE with shock or syncope
Major PE with right-ventricular dysfunction
Major PE with normal right-ventricular function
Minor PE
Goldhaber, 1999
Nass et al, 1999
Recommended Treatment of Acute PE
Massive PE with shock or syncope
Thrombolysis or surgery
Major PE with right-ventricular dysfunction
Anticoagulants (Dalen)
Thrombolysis (Goldhaber)
Major PE without right-ventricular dysfunction
Anticoagulants
Minor PE
Anticoagulants
Hyers et al, 1998
Goldhaber, 1999
Goldhaber, 1998
Dalen et al, 1997
Nass et al, 1999
Thrombolysis for Massive PE
Heparin (10,000 U bolus + 1000 U/hr IV) versus
streptokinase (1.5 million U IV over 60 min) + heparin

Patients (8)
Cardiogenic shock; HR 124; Pa0
2
46
(4/4 heparin patients had already deteriorated on heparin)

Heparin Streptokinase + Heparin
Mortality 4/4 0/4
Jerjes-Sanchez et al, 1995
Randomized Trial of Alteplase versus
Heparin in Normotensive Patients
With Acute PE
Recurrent PE
Death
Heparin
(n=55)
5 (9%)
Alteplase
(n=46)
0
P
0.06
All events occurred in patients with right-ventricular dysfunction.
2 (3.6%) 0
Goldhaber et al, 1993
Management Strategy and Prognosis
for Pulmonary Embolism (MAPPET)
Konstantinides et al, 1997
719 patients without cardiogenic shock
169 received thrombolytic therapy:
30-day mortality 4.7%; recurrent PE 7.7%;
major bleeding 21.9%
550 received heparin:
30-day mortality 11.1%; recurrent PE 18.7%;
major bleeding 7.8%
Heparin or Thrombolysis in
Hemodynamically Stable Major Acute
PE With Right-Ventricular Dysfunction
PE recurrence %
Bleeding %
Severe
Intracranial
Death %
Thrombolysis
(n=64)
15.6
4.7
Heparin
(n=64)
0
0
P
0.001
0.24
128 consecutive patients (matched but not randomized)
between 1992 and 1997
Hamel et al, 1998
9.4 0 0.028
6.25 0 0.12
4.7 4.7 1.0
Pulmonary Embolectomy
Can be life saving in patients with massive PE.
In consecutive series of 96 patients, mortality
was 37% (Meyer et al, 1991).
Cardiac arrest and associated cardiopulmonary
disease were independent predictors of death.
Elective pulmonary embolectomy was life saving
in selected patients with chronic thromboembolic
pulmonary hypertension (Moser et al, 1990).
Randomized Trial of Caval Interruption
Initial benefit in preventing PE offset by excess
of recurrent DVT in the longer term in the
absence of anticoagulant.
Therefore, caval filter not recommended for this
patient population in the long term.
Decousus et al, 1998
Evaluation of Inferior Venacaval Filter in
Patients With Proximal Venous Thrombosis
Symptomatic PE at day 12
Total PE at day 12
Recurrent DVT at 2 years
IVC Filter
2
37 (20.8%)
No Filter
5
21 (11.6%)

2 (1.1%)
9 (4.8%)*
All patients received 3 months of anticoagulants; primary end-point data
unavailable for 28 patients.
*P=0.03

P=0.02
Decousus et al, 1998
Treatment of VTE
Anticoagulants
Thrombolytic Therapy
Caval Interruption
Surgical Removal
Issues for Future Research
Optimal duration of anticoagulant therapy
Lower therapeutic range for warfarin
Relative efficacy and safety of new oral
small-molecule direct thrombin inhibitor*
versus warfarin
Role of thrombolytic therapy for treatment
of DVT and PE
* The new oral small-molecule direct thrombin inhibitor does not have FDA approval for any indication.