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14% pts/y in patients with both alterations)
(24).
Implications for secondary
prevention of VTE
A number of clinical trials have been
devoted to the problem of "optimal duration"
of oral anticoagulant therapy
(OAT) after a first or a second episode
of VTE. "Optimal duration" of oral anticoagulant
therapy should warrant effective
and long lasting protection from
VTE recurrences combined with a minimum
risk of bleeding. Four main
trials on this subject have been thoroughly
reviewed in the Cochrane Library
(25). Recurrent VTE was effectively
prevented only while oral anticoagulants
were actually given. Although
the relative risk reduction for recurrences
remained constant, the absolute
risk decreased over time due to its already
mentioned spontaneous decline.
Hence, the efficiency of OAT tends to
decrease with exceeding prolongation,
as the hemorrhagic risk correspondently
increases with duration. The
WODIT study (26), on patients with
idiopatic proximal DVT treated either
for 3 or 12 months showed in fact that
recurrences were effectively prevented
only while oral anticoagulants were given.
At the three years follow-up term
there was indeed no difference in the
total number of recurrences between
the short and long duration group.
Long-term or life-long prolongation
should therefore be limited to patients
at very high risk of recurrences, and
until the risk of bleeding complications
remains acceptable.
The problem of the risk-benefit ratio of
prolonged OAT has been investigated
in the "PREVENT" study (27), in which
patients with idiopathic VTE wen randomized
to continue OAT with a lowintensity
regimen (INR 1.5-2) after
completing a course of regular treatment.
After a mean treatment duration
and follow-up of 2,1 y the low regimen
patients showed a considerable risk reduction
versus placebo. However most
recently a direct comparison between
low and regular anticoagulant regimen
after a standard treatment period confirmed
the superiority of the regular over
the low-regimen management (27).
Finally, we believe that the choice of
the duration or the option of re-starting
OAT may be influenced in the future
by the "predictability" of recurrences,
but a specific study of intervention is
needed in that respect.
Alternatives to oral
anticoagulants in secondary
prevention of VTE
LMW heparins have been evaluated in
several studies as an alternative for
long-term treatment of VTE. In a metaanalysis
of seven trials van der Heijden
et al (29) found that the reduction in
risk of VTE under long-term LMWH
treatment was no different from that
seen with OAT, while the differences in
bleeding significantly favoured LMWH.
The main problem of clinical application
of these trials is their uncertain indication
regarding the dose of LMW
heparin. Although LMW heparins
seem potentially as effective as coumarins
in preventing recurrences, and
may even be safer, they are more expensive,
have practical drawbacks, and
their posology is uncertain (28). Thus,
vitamin K antagonists currently remain
the treatment of choice for secondary
prevention of VTE.
The new orally active direct thrombin
inhibitor Ximelagatran is the most likely
future candidate to substitute for coumarin
drugs in the treatment of VTE
(31). The perspective of using one single
drug from the acute to the postacute
and the chronic phases of DVT
without the burden of laboratory control
is certainly attractive, but needs definite
and detailed confirmation in the
complex family of trials under way in
these indications.
REFERENCES
1. Heit JA, Silverstein MD, Mohr DN, Petterson
TM, Lohse Ch M, O'Follon M,
Melton LJ. The epidemiology of venous
thromboembolism in the community.
Thromb Haemost 2001; 86: 452-463
S. Coccheri
Venous Thromboembolism
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