Anticoagulant therapy
for venous thromboembolism was implemented in the 1940's after experimental studies
showed the ability of heparin and coumarinic substances to prevent the development
of thrombi in different experimental models. Despite methodological problems,
the study carried out by Barrit and Jordan,1 published
in 1960, showed an extremely high mortality rate among patients with pulmonary
embolism (PE) who were not treated with anticoagulants comparatively to those
who received these drugs. At that time, the use of placebo or nontreatment of
patients with PE in control groups in clinical studies was considered unethical.
Later studies, which compared patients with deep vein thrombosis (DVT) of the
lower extremities treated with different doses of heparin with those treated with
adequate doses of anticoagulants, clearly showed that this treatment should be
well implemented in order to avoid recurrence of the disease.2
Therefore, there is no doubt that, today, anticoagulant therapy in adequate doses
is essential for the treatment of both DVT and PE and that the nonuse of this
therapy in the absence of any contraindications is considered unethical.
Since
the pharmacological effect of anticoagulants slightly changes hemostatic balance
and as heparin and antagonists of vitamin K (AVK), anticoagulant agents used in
the last 60 years, have their pharmacokinetics altered by intrinsic and extrinsic
factors, according to the experimental studies mentioned above, it is necessary
to monitor their effects in order to maintain an adequate coagulation level and
obtain an antithrombotic effect without increasing the risk of hemorrhage. Experimental
and clinical studies determined these levels at 2 or 2.5 times those of normal
coagulation, in which heparin is mainly monitored by activated partial thromboplastin
time (APTT) and AVK is controlled by prothrombin time (PT). With the aim of internationally
standardizing PT so as to allow for the comparison between protocols and conducts,
the World Health Organization created, in the 1980's, a standard thromboplastin
and a standardized method for expressing PT results, the so-called international
normalized ratio (INR). This standard should be adopted by all physicians and
laboratories that deal with anticoagulation.
At
the end of the last century, several clinical assays were carried out in order
to determine the ideal length of anticoagulation therapy, with either initial
heparin or AVKs in the long term. Nowadays, there is a consensual agreement that
heparinization could be maintained for only five to seven days (along with AVKs)
in most cases, and that long-term anticoagulation should not be less than 12 weeks
and, if necessary, it should be permanently maintained. This period depends on
the presence of triggering factors for thrombosis, risk maintenance factor, previous
episodes of VTE and presence of thrombophilia.
In
the 1990's, the first advance in anticoagulant therapy was made within a 50-year
period - the introduction of low molecular weight heparin (LMWH). The higher bioavailability
and longer half-life of LMWH allows its routine use subcutaneously, with doses
established according to patient's weight, and without the need of laboratory
control in most cases. This helped to simplify anticoagulant therapy, in addition
to offering selected patients home treatment for DVT, thus facilitating and humanizing
the treatment and also reducing its total cost. It has been suggested, but yet
not confirmed, that the mortality rate of patients treated with LMWH, especially
those with cancer, is lower.3
In
the late 20th century, the concept of VTE prophylaxis, especially pharmacological
prophylaxis, also based on hundreds of controlled clinical assays, was consistently
introduced with minidoses of heparin and LMWH. These measures helped mitigate
the morbidity and mortality of clinical and surgical patients, thus reducing the
necessity for the treatment of installed VTE and minimizing the costs associated
with the disease.
What
is the perspective of anticoagulant therapy in the early 21st century? Researchers
and the pharmaceutical industry are in a constant search for an ideal anticoagulant
substance. Such a substance should offer maximal antithrombotic activity and minimal
risk of hemorrhage and side effects; its administration should occur by any route,
depending on the patient's clinical status; no laboratory control should be necessary;
the drug should be easily neutralizable in case of complication or emergency;
it should be comfortable for the patient and for the medical staff; it should
be inexpensive so that most patients can buy it and use it. Therefore, the cost-risk-benefit
ratio should be better than that of currently available drugs. Several medications
are being tested at the moment, and we hope they can meet most of these requirements,
but unfortunately we have no definitive answers yet. Some of these drugs, such
as hirudin and argatroban, were marketed but they are a far cry from outperforming
currently available medications; they can, however, replace them in special cases
as in heparin-induced thrombocytopenia.4
This
way, in the mid-2002, the use of anticoagulants as the single or complementary
treatment for VTE is required in special cases in which venous thrombectomy or
fibrinolytic agents are recommended. The only reason for not using anticoagulants
is medical contraindication, when vena cava filter placement should be considered,
in cases of severe DVT of the lower limbs. The current recommendation is to begin
the treatment with heparin or with an LMWH and continue it with AVK. In the future,
maybe not so remote, new substances will be able to improve or at least simplify
this treatment.
1.
Barrit DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism:
a controlled clinical trial. Lancet 1960;1:1309-12.
2.
Hull RD, Rascob GE, Pineo GF. Overview of treatment of venous thromboembolism.
In: Hull RD, Raskob GE, Pineo GF, editores. Venous thromboembolism: an evidence-based
atlas. Armonk: Futura; 1996. p. 221-4.
3.
Gould MK, Dembitzer AD, Sanders GD, Garber AM. Low-molecular-weight heparins compared
with unfractionated heparin for treatment of acute deep venous thrombosis. A cost-effectiveness
analysis. Ann Intern Med 1999;130:789-99.
4.
Weitz JI, Hirsh J. New anticoagulant drugs. Chest 2001;119 Suppl 1:95-107.
