Highlights from the International Consensus Statement: Guidelines According to Scientific Evidence
Professor A N Nicolaides, Emeritus Professor of Vascular Surgery, Department of Surgery, Imperial College, London, UK, and Special Scientist, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus, and Dr J Fareed Professor of Pathology and Pharmacology. Director of Hemostasis and Thrombosis Research Laboratories, Loyola University Medical Center, Maywood Il, USA
In North America and Europe the annual incidence of deep vein thrombosis (DVT) is 160 per 100,000 population and the prevalence of venous ulceration is at least 300 per 100,000 of which approximately 25% are due to DVT (1). Estimates of the overall annual costs of chronic venous insufficiency vary from 600 to 900 million euros in Western countries representing 1 to 2% of the total healthcare budget.
The aims of treatment of DVT are to prevent death and disability from pulmonary embolism (PE), recurrence of DVT and the development of the post-thrombotic syndrome. The latter is the result of persistent venous obstruction and/or reflux from damaged venous valves.
DVT, other than that triggered by trauma or surgery, is now considered to be a chronic disease with a high risk of recurrence as a result of minor provocations. Recurrence is more likely to produce the post-thrombotic syndrome than a single DVT episode. It has been suggested that the risk of recurrence may be higher in the presence of residual thrombus or elevation of D-dimer.
A recently published evidence-based document (Prevention and treatment of venous thromboembolism. International consensus statement. Int Angiol 2006;25:101-161) has provided guidelines and recommendations on the prevention and/or management of venous thromboembolism. The strength of each recommendation has been graded as A, B, or C depending on the corresponding level of evidence I, II or III. Because the definitions of levels of evidence vary slightly in each document the following definitions are used in this editorial which is confined to the management of DVT.
Level 1: data from randomised controlled trials (more than one) with consistent results, which are directly applicable to the target population.
Level II: data from randomised controlled trials with less consistent results, limited power or other methodological problems, which are directly applicable to the target population; also data from a well conducted high quality single trial or from consistent randomised controlled trials extrapolated from a different group of patients to the target population.
Level III: data from well-conducted observational studies with consistent results, directly applicable to the target population.
Diagnosis of DVT
The clinician should maintain clinical vigilance and always consider the possibility of DVT, which may occur with calf pain or mild symptoms such as ankle swelling. It should be remembered that approximately 15% of patients presenting with superficial vein thrombosis have concurrent DVT. Because only half of the patients presenting with symptoms and signs suggestive of DVT actually have DVT, the diagnosis needs to be confirmed with an objective test. Ultrasonic duplex scanning is now the key imaging test. In patients with low DVT probability “Wells criteria” a negative D-dimer test will rule out DVT but in a patient at intermediate or high DVT probability, a negative D-Dimer is insufficiently sensitive to exclude DVT. In clinical practice D-Dimer testing of low probability patients can reduce the number of duplex scans by 30%. A positive D-Dimer is of no value because D-dimer may be elevated by many other conditions such as myocardial infarction, cancer, sepsis, trauma or pregnancy.
Initial anticoagulation therapy
randomised controlled trials have demonstrated that treatment with single daily doses of low molecular weight heparin (LMWH) given subcutaneously is superior to unfractionated heparin (UH) (grade A). This is because LMWH is associated with a lower mortality, reduced episodes of bleeding and heparin induced thrombocytopenia (HIT). In addition, it is cost effective mainly because it minimises or avoids hospital stay. Out patient treatment is at least as safe as inpatient treatment provided the symptoms allow it and the required support services for converting to oral anticoagulants are in place. Evidence is accumulating that LMWH and normal ambulation produces better recanalisation than treatment using iv. UH with the associated confinement to bed. Another advantage of LMWH is that it has a consistent dose response making monitoring unnecessary. A disadvantage is the inability to reverse its action in the presence of haemorrhage.
Regulatory bodies in Europe and North America now consider the various LMWHs to be distinct drug products. They require clinical validation for specific indications for each drug and each LMWH must be dosed according to the manufacturers’ recommendations. The dose recommended for each product has the optimum benefit/risk ratio as shown by clinical trials. Thus, therapeutic interchange of dosage among products is not appropriate.
Initial therapy with vitamin-K-antagonists alone is associated with an unacceptable high rate of recurrence. Initial LMWH and subsequently long-term oral anticoagulation are both necessary (grade A). An initial loading dose of 5 or 10mg of vitamin-K-antagonist is started when the diagnosis is confirmed. LMWH is discontinued on the 5th day provided the INR remains in the therapeutic range (2.0-3.0) for at least two consecutive days.
Graduated elastic stockings
Immediate mobilisation with graduated compression stockings worn for at least two years at an ankle pressure of 30-40mm Hg (Class II) leads to a more rapid reduction of pain and swelling and reduces the occurrence of the post-thrombotic syndrome by at least 50% (grade A).
Duration of vitamin-K-antagonist therapy
The duration of therapy depends on whether it is the first episode or recurrence of DVT, whether there are transient or continuing predisposing risk factors and on the risk of bleeding.
When calf DVT is diagnosed secondary to a transient risk factor it is recommended that patients be treated with LMWH followed oral anticoagulants for three months. Idiopathic calf DVT should be treated for a longer period in order to reduce the risk of recurrence (see below) (grade A).
When DVT extends proximal to the knee as first episode oral anticoagulants should be continued for at least 6-12 months (grade A). In the presence of antihospholipid antibodies or in the presence of two or more relatively mild thrombophilic conditions (eg. combined factor V Leiden and prothrombin 20210 gene mutations) anticoagulation should be for at least 12 months (grade C). When a more severe thrombophilia such as deficiency of antithrombin, protein C or protein S is present indefinite therapy is recommended (grade B).
For patients with two or more episodes of DVT not induced by trauma or surgery indefinite treatment is recommended (grade A). However, in patients who receive indefinite anticoagulation therapy, the risk-benefit of continuing treatment should be reassessed at least annually. The patient should, if appropriate, be involved in the decision process.
LMWH as an alternative to vitamin-K-antagonist
Nine randomised controlled trials have demonstrated that the safety and efficacy of treatment with therapeutic doses of LMWH (in most studies for three months) is similar to vitamin-K-antagonists. Thus, LMWH is an alternative option in patients in whom INR control is difficult (grade A). Two randomised controlled studies have shown that LMWH (three months in one and six months in the other) is more effective in reducing recurrent DVT than oral anticoagulants in patients with cancer (grade A).
Inferior vena cava filters
There is insufficient evidence for the efficacy of inferior vena cava filters in reducing PE, but there is clear evidence that they increase the recurrence of DVT despite oral anticoagulation. Thus, currently inferior vena cava filters should be used mainly in patients with PE or proximal DVT who have contraindications to anticoagulation; also in patients who have suffered recurrent PE while on adequate therapeutic anticoagulation (grade C).
Catheter directed thrombolysis
Systemic thrombolysis is not recommended because it is associated with high bleeding rates and allergic reactions as shown by many studies in the 1970s and 1980s. In contrast, catheter-directed thrombolysis where the thrombolytic agent is delivered into a clot is associated not only with complete lysis in a high proportion of patients (72%) but also with a lower complication rate, improved quality of life improved vein patency and valve function. Catheter directed thrombolysis should be considered in young patients with iliofemoral thrombosis at low risk of bleeding in specialised centers experienced with the procedure. More studies are needed before recommendations for more general use can be made (see below).
Treatment of DVT during pregnancy
The evidence for treatment of DVT during pregnancy is not adequate for definitive recommendations because it is based mostly on observational studies. However, it is established that vitamin-K-antagonists cross the placenta and are associated with fetal malformations between 6-12 weeks of pregnancy. They are also associated with fetal bleeding including intracerebral hemorrhage at delivery. In contrast, LMWH does not cross the placenta and is currently the method of choice. Women who become pregnant while receiving vitamin-K-antagonists should immediately change to LMWH.
The need for further studies
The systematic reviews of the literature undertaken in order to define the levels of evidence have identified a number of areas where evidence is lacking, indicating a number of key questions that need to be addressed in future studies. These are listed below.
1. Randomised studies comparing catheter directed thrombolysis of proximal DVT with conventional anticoagulation therapy at preventing the post-thrombotic syndrome are required; also to determine the type of patient that would benefit most.
2. Studies should investigate the efficacy of protamine sulphate in patients bleeding from LMWH.
3. The role of long term LMWH (more than three months) versus vitamin-K-antagonists in the treatment of DVT and prevention of post-thrombotic syndrome should be determined by randomised controlled trials.
4. The value of prognostic markers such as D-dimer, Prothrombin Fragment F1.2 and extent of residual clot burden in guiding the duration of long-term oral anticoagulation needs to be determined.
Several new drugs including oral and parenteral anti-Xa and antithrombin agents are in advanced clinical stages of development. Parenteral antithrombin agents such as argatroban and hirudin are already in use for the management of heparin compromised patients (grade C). These new drugs aim to replace the conventional oral anticoagulants and LMWHs in the treatment of DVT. However, several factors such as increase in liver enzymes, QT wave prolongation and dose response may limit their development for this indication. Moreover, DVT represents a complex pathophysiologic syndrome with multiple etiologies, which may prove to be treatable only by drugs with multiple actions such as LMWHs and vitamin-K antagonists.