Panel \# 4

Treatment of Venous Thromboembolism; Anticoagulants

by

Kenneth A. Bauer, M.D.

From the VA Boston Healthcare System and Beth Israel Deaconess Medical
Center,

Harvard Medical School, Boston, Massachusetts, USA

Address reprint requests to Kenneth A. Bauer, M.D., VA Boston Healthcare
System, 1400 VFW Parkway, West Roxbury, MA 02132 or
kbauer@bidmc.harvard.edu

The primary anticoagulants currently used to treat acute venous
thromboembolism (VTE) are unfractionated heparin (UFH) and
low-molecular-weight heparin (LMWH). By accelerating the action of
antithrombin, these agents exert a prompt antithrombotic effect that
prevents thrombus extension. While they do not directly dissolve
thrombi, they allow the fibrinolytic system to proceed unopposed and
more readily reduce the size of the existing blood clots. For initial
treatment of VTE, a minimum of 5 days of treatment is required with UFH,
which is usually given by a constant intravenous infusion, or LMWH,
administered subcutaneously. LMWH preparations have advantages over UFH.
These include superior bioavailability such that they do not require
laboratory monitoring of coagulation in most patients, which is required
for UFH. They also have a longer half-life and can be administered once
or twice daily. Lower rates of heparin-induced thrombocytopenia (HIT)
occur with LMWH than with UFH. LMWH is as least as effective and as safe
as UFH for the initial treatment of deep venous thrombosis (DVT) and
pulmonary emboli (PE). A major advantage of LMWH is that therapy for DVT
can be done entirely in the outpatient setting, or with only a brief
hospitalization to assure that subcutaneous injections can be reliably
administered at home.

Fondaparinux is a synthetic form of the pentasaccharide sequence on UFH
and LMWH that mediates their interaction with antithrombin. It
accelerates the inactivation of only activated factor Xa, but not
thrombin, in the coagulation cascade. This distinguishes fondaparinux
from UFH and LMWH, which are able to inhibit multiple activated clotting
factors (e.g., thrombin, factor Xa, factor IXa) by interacting with
antithrombin. Fondaparinux has a longer half-life than LMWH and is
administered subcutaneously once daily for all clinical indications. It
does not require laboratory monitoring and is unlikely to cause
heparin-induced thrombocytopenia. Fondaparinux is approved for the
initial treatment of DVT and PE.

Following an episode of VTE, oral anticoagulation is initiated and this
can be done on the first day of treatment. The only approved oral
anticoagulants at the present time are thevitamin K antagonists, and
warfarin is virtually exclusively used in the United States. Vitamin K
antagonists interfere with -carboxylation of glutamic acid residues of
four clotting factors produced by the liver that promote blood
coagulation, factors VII, IX, X, and prothrombin. Prothrombin has the
longest half-life of these four clotting factors and a substantial
reduction in its activity is required for warfarin to exert its
antithrombotic effect. For this reason, overlap of warfarin with UFH,
LMWH, or fondaparinux is needed for at least 4-5 days is required in
patients with acute DVT or PE. When used at appropriate doses, UFH,
LMWH, and fondaparinux followed by warfarin are highly effective in
preventing recurrent VTE while patients remain on therapy.

The vitamin K antagonists, however, have a number of limitations; these
are shown along with their respective consequences in Table 1. An
"improved" oral anticoagulant that is at least as effective as warfarin
in preventing thrombus formation and at least as safe with respect to
bleeding risk is therefore needed. The characteristics of such an oral
medication include good oral bioavailability, predictable anticoagulant
response, rapid onset of action, a wide therapeutic window, no food or
drug interactions, and no unexpected toxicities (e.g., hepatic
dysfunction). A number of such agents are under development, which
directly inhibit single activated coagulation factor such as factor Xa
or thrombin. The oral factor Xa inhibitors include rivaroxaban (BAY
59-7939) and LY517717, and dabigatran is an oral direct thrombin
inhibitor. In several randomized clinical trials, the direct thrombin
inhibitor, ximelagatran, without coagulation monitoring, was shown to be
as efficacious and safe as warfarin in the prevention and treatment of
venous thromboembolism as well as in the prevention of stroke in
patients with atrial fibrillation . Approximately 6% of patients treated
with ximelagatran for more than 2 months developed a transient increase
in liver function (as manifested by a greater than 3-fold elevation in
alanine aminotransferase levels) that was usually asymptomatic and
reversible whether or not the drug was discontinued. This "unexpected"
toxicity was a major reason for the drug's not receiving approval from
the U.S. Food and Drug Administration.

Several parenteral direct thrombin inhibitors are available, but are
generally used only for the prevention or treatment of thrombosis in
patients with heparin-induced thrombocytopenia. The two agents that have
been approved for treatment of heparin-induced thrombocytopenia are
recombinant hirudin (i.e., lepirudin) and argatroban, a synthetic
L-arginine derivative. These agents must be monitored by the clinical
laboratory with the activated partial thromboplastin time.

Following initial treatment of acute VTE with parenteral UFH, LMWH, or
fondaparinux at therapeutic doses, standard therapy includes warfarin at
an INR between 2 and 3 for a period of 3 to 12 months; this results in
more than a 95% reduction in risk of recurrent venous thromboembolism.
The cumulative incidence of recurrent venous thrombosis following
cessation of therapy in patients with a first unprovoked episode of
symptomatic venous thromboembolism is 5% to 15% at 1 year and
approximately 25% at 5 years . Recurrences are much less frequent when
the initial event is associated with a transient risk factor (for
example, surgery, trauma, oral contraceptive use or pregnancy) and
anticoagulation can be discontinued after 3 to 6 months if the
triggering factor is no longer present regardless of whether a
hereditary thrombotic defect is identified. Despite this recurrence
risk, chronic anticoagulation with warfarin at an INR of 2-3 beyond 3-12
months is not felt to have sufficient benefit relative to its major
bleeding risk to support long-term prophylaxis for all patients at
substantial recurrence risk. Cohort studies of patients on oral
anticoagulants at an INR 2-3 monitored by anticoagulation clinics report
an annual major bleed rate of approximately 2%, which can rise among
elderly patients to 7% to 9% per year .

For the individual patient, the decision to continue anticoagulation
indefinitely therefore requires estimation of the quantitative risk of
recurrent thrombosis (including fatal pulmonary embolism) and major
bleeding (including fatal bleeding) over time. Clinical factors such as
the site of thrombosis (pulmonary emboli versus deep venous thrombosis)
should be factored into the decision. Patient compliance has a major
impact on the success of therapy, and patient preferences must be
factored into the decision. A substantial amount of data has been
accumulated with respect to the risk of recurrence in patients with an
initial unprovoked venous thrombotic event who are heterozygous carriers
of the factor V Leiden or prothrombin G20210A mutations and it does not
appear to be significantly higher than among noncarriers . The
recurrence risk does appear to be significantly higher in the small
subset of patients who are heterozygous for both mutations, homozygous
for factor V Leiden, or have two hereditary thrombophilic defects (for
example, antithrombin, protein C, or protein S deficiency and
heterozygosity for the factor V Leiden mutation). Deficiencies of
antithrombin, protein C, or protein S are encountered relatively
infrequently, and information is not available on the recurrence rates
in unselected cohorts with an initial unprovoked venous thromboembolism.
Clinicians with expertise in this area, however, often recommend that
patients with heterozygous antithrombin deficiency receive
anticoagulation for an indefinite period of time because they appear
more prone to thrombosis than patients with other single heritable
abnormalities. Some also recommend such an approach for patients with
heterozygous deficiencies of protein C and protein S.

Patients with unprovoked VTE in association with antiphospholipid
antibody syndrome require indefinite anticoagulation due to a high risk
of recurrent thrombosis off anticoagulants. Patients who develop
symptomatic venous thromboembolism in the setting of an active
malignancy are at increased risk for recurrent venous thrombosis and
bleeding when treated with standard anticoagulant regimens (i.e, initial
treatment with heparin or low-molecular-weight heparin followed by
warfarin) . A randomized clinical trial in active cancer patients with
symptomatic venous thromboembolism demonstrated that continued therapy
with low molecular weight heparin administered once daily in lieu of
warfarin reduced the risk of on-treatment recurrence by approximately
50% at 6 months as compared to standard anticoagulant therapy . Patients
whose thrombosis is associated with malignancy should generally be
anticoagulated as long as the cancer is active.

There is a need for improved methods to identify patients at highest
risk for developing recurrent venous thromboembolism who require
long-term anticoagulation; assessment of D-dimer levels at the
completion of anticoagulant therapy are under evaluation for this
purpose .

Given the efficacy of standard intensity warfarin in preventing
recurrent VTE following a venous thrombotic event, it was logical to
investigate whether long-term low-intensity warfarin reduced the risk of
major bleeding without substantially reducing its antithrombotic
efficacy. Two randomized clinical trials were conducted in patients with
idiopathic venous thromboembolism to determine the efficacy and safety
of extended low-intensity warfarin at an INR of 1.5-2 in preventing
recurrent events . While both trials demonstrated that low-intensity
warfarin offers substantial protection against recurrent venous
thromboembolism, only one of the trials included a standard intensity
arm (i.e., INR 2-3) ; this arm showed a significantly lower recurrence
rate and a major bleed rate that, surprisingly, was similar .to the
low-intensity arm. The Seventh American College of Chest Physicians
(ACCP) Conference on Antithrombotic and Thrombolytic Therapy therefore
recommends that patients requiring extended anticoagulation receive
standard intensity warfarin .

References

Table 1. Limitations of Vitamin K Antagonists

+----------------------------------+----------------------------------+
| #### Limitation                  | #### Consequence                 |
+----------------------------------+----------------------------------+
| Slow onset of action             | Overlap with a parenteral        |
|                                  | anticoagulant                    |
+----------------------------------+----------------------------------+
| Genetic variation in metabolism  | Variable dose requirements       |
+----------------------------------+----------------------------------+
| Multiple food and drug           | Frequent coagulation monitoring  |
| interactions                     | (INR)                            |
+----------------------------------+----------------------------------+
| Narrow therapeutic index         | Frequent coagulation monitoring  |
|                                  | (INR)                            |
+----------------------------------+----------------------------------+
|                                  |                                  |
+----------------------------------+----------------------------------+

##### Table 2. Duration of Anticoagulation in Patients with Venous Thromboembolism

First event with reversible or time limited risk factor 3-6 months

Unprovoked first or second event 3-12 months

then consider indefinite anticoagulation at INR 2-3

Special Situations

First event in association with

active cancer Consider chronic LMWH

antiphospholipid antibody syndrome Indefinite (warfarin INR 2-3)

antithombin deficiency or multiple Indefinite (warfarin INR 2-3)

genetic defects, ? deficiencies of

protein C or protein S