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Duration of Anticoagulation in Venous
Thromboembolism
Arch Intern Med. 2003;163:1265-1266.
ORAL
ANTICOAGULATION with a vitamin K (phytonadione) antagonist
has always been a problematic therapy. The risk of serious
bleeding is substantial (2%-3% yearly) and does not
decrease over time. In fact, as patients undergoing
long-term therapy age, the bleeding risk increases. The
therapeutic effect of oral anticoagulation falls in a
narrow range between increased risk of thrombosis when
the international normalized ratio (INR) is too low and
increased bleeding risk when it is too high.
Because of multiple drug and dietary interactions with
vitamin K antagonists, therapy must be frequently
monitored and the dose of drug adjusted. Patients must
make substantial lifestyle changes to cope with the
increased bleeding risk and the need for monitoring.
Patients with atrial fibrillation or a mechanical heart
valve have a permanent risk of thrombotic stroke, and the
bleeding risk and inconvenience of oral anticoagulation
must be accepted. However, in patients with venous
thromboembolism (VTE), the risk of recurrent
thromboembolism seems to decline with time after the
index event. Caregivers and patients wrestle continuously
with the question of duration of therapy. Unfortunately,
evidence-based recommendations on duration of therapy are
often long on recommendations and short on
evidence.1
In this issue of the ARCHIVES, van Dongen and colleagues2
publish a meta-analysis that attempts to give some
scientific rationale for the duration of therapy for VTE.
Their effort is admirable but is hamstrung by the dearth
of suitable studies on duration of therapy. This
statement is illustrated by the fact that 83 of 118
studies initially deemed appropriate for analysis had to
be discarded because of absence of information on the timing
of recurrence after cessation of anticoagulation. A
further hindrance is the fact that many of the remaining
studies did not adequately characterize the risk status
of the patients included. These studies offered only
general descriptions of risk status such as history of
VTE, the presence of cancer, other permanent risk
factors, or transient risk factors.
Nevertheless, some useful generalizations can be derived.
First, van Dongen and colleagues confirm that the risk of
recurrence decreases over time after cessation of
anticoagulation, becoming quite low after 9 months. This
statement applies to durations of anticoagulation the
authors classify as short (4-6 weeks), medium (3 months),
and long (4-6 months). Second, with few exceptions,
recurrence of VTE is inversely related to duration of
anticoagulation, being highest in the group that receives
the shortest duration of anticoagulation.
Although the authors do not describe the individual risk
factors that contribute to recurrence, other researchers
have shown that patients with idiopathic or primary
disease are at high risk of recurrence.3-4
From these findings, general recommendations can be made
about duration of anticoagulation. First, patients with
an initial episode of VTE secondary to a transient risk
factor such as surgery, trauma, immobilization, or
estrogen use need undergo only a short period of
anticoagulation. Although the precise duration is
unknown, 3 to 6 months is a useful approximation. Second,
patients with idiopathic disease require a longer period
of anticoagulation, although the precise duration is again
unknown. Furthermore, recent studies suggest that longer
periods of anticoagulation only delay the time to
recurrence.5-6
Despite this caveat, a useful approximation for a first
event of idiopathic VTE is at least 6 months, although
some authorities recommend even longer periods of
anticoagulation. In this regard, a recent study indicates
that after 6 months of anticoagulation to an INR of 2.0
to 3.0, subsequent anticoagulation to an INR of 1.5 to
2.0 results in a very low incidence of recurrent VTE with
negligible bleeding.7
These 2 recommendations have some rational basis, but
thereafter the medical evidence on duration of therapy is
quite deficient. Patients with recurrent VTE usually
undergo anticoagulation therapy for longer than 6
months.8
Patients with a first event and familial thrombophilia
such as antithrombin deficiency or protein C or S
deficiency usually undergo anticoagulation therapy for a
year or longer.9-10
Patients with a first event and an antiphospholipid
antibody manifested as a lupus anticoagulant are at high
risk of recurrence and seem to require extended or
permanent anticoagulation.11
In contrast, patients with a first episode who are
heterozygous for factor V Leiden or the prothrombin
mutation and have a transient risk factor such as surgery
seem to require only 3 to 6 months of therapy. However,
there are few controlled studies of treatment duration in
any of these subgroups.
What can be done to address this lack of knowledge?
Controlled trials are needed on duration of therapy in
individual risk groups, particularly in patients with
cancer. Furthermore, investigators who perform future
treatment trials in VTE should carefully characterize the
individual risk status of their study patients and
observe them for at least a year after cessation of
anticoagulation to determine the rate and timing of
recurrent disease. Only with this information can we make
stronger recommendations about the duration of
anticoagulation in individual patients with VTE. In the
meantime, decisions about duration of therapy must
incorporate full discussion of risks and benefits of
anticoagulation and consideration of individual patient
preferences in this regard.
Thomas M. Hyers, MD
St Louis University
School of Medicine
CARE Clinical Research
533 Couch Ave, Suite 140
St Louis, MO
63122
(e-mail: thyers@careinternet.com)
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TEXT
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van Dongen CJJ, Vink R, Hutten BA, Büller HR, Prins MH. The
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vitamin K antagonists in relation to time since first event: a
meta-analysis. Arch Intern Med. 2003;163:1285-1293. ABSTRACT/FULL TEXT
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Schulman S, Rhedin AS, Lindmarker P, et al, for the Duration of
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venous thromboembolism. N Engl J Med. 1995;332:1661-1665. ABSTRACT/FULL TEXT
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Kearon C, Gent M, Hirsh J, et al. A comparison of three months of
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Agnelli G, Prandoni P, Santamaria MG, et al, for the Warfarin
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Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term,
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Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral
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van den Belt AG, Sanson BJ, Simioni P, et al. Recurrence of venous
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Hirsh J, Kearon C, Ginsberg J. Duration of anticoagulant therapy
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MEDLINE
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Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of
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Med. 1995;332:993-997. ABSTRACT/FULL TEXT
RELATED ARTICLES IN ARCHIVES OF INTERNAL
MEDICINE
The
Incidence of Recurrent Venous Thromboembolism After Treatment With
Vitamin K Antagonists in Relation to Time Since First Event: A
Meta-analysis
Carlo J. J. van Dongen, Roel Vink, Barbara
A. Hutten, Harry R. Büller, and Martin H. Prins
Arch Intern
Med. 2003;163:1285-1293.
ABSTRACT
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TEXT
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