Intensity and duration of oral anti-coagulation therapy in venous thrombo-embolism
J. F. Lassen and Prof. S.D. Kristensen
Aarhus, Denmark
Member and Vice-chairman and of the working group on Thrombosis
After initial medium-intensity warfarin therapy for 6 months (INR 2.0-3.0), long-term, low-intensity warfarin therapy (INR 1.5-2.0) is superior to placebo in patients with idiopathic venous thrombo-embolism.
Anti-coagulation (AC) therapy with heparins followed by oral vitamin K-antagonists is recommended after deep venous thrombosis (DVT) and pulmonary embolism. The bleeding risk is related to the duration and intensity of AC therapy. A target INR of 2.0-3.0 is as effective as high-intensity AC therapy with target INR of 3.0-4.5 and causes less bleeding (1). This intensity of AC therapy is usually recommended after DVT or pulmonary embolism.
Recommended duration of therapy is: 1) in patients with reversible or time-limited risk factors: 3 months of AC therapy, 2) first episode of idiopathic venous thrombo-embolism: at least 6 months 3) recurrent idiopathic venous thrombo-embolism or long-term risk factors: 12 months or life-long (2). In case persistent DVT and verified on a duplex scan after e.g. 6 months of therapy, one might consider prolonged AC therapy. Initiation of AC therapy with a loading dose is often used. However, this approach does not necessarily bring the therapy more quickly into the therapeutic range.
Recently, Ridker and co-workers assessed the effects of low intensity warfarin (target INR 1.5-2.0) in patients with idiopathic venous thrombo-embolism (3). The 508 patients were all treated with full-dose AC therapy for at least 6 months (median 6.5 month) and then randomised to low-intensity warfarin or placebo and followed for up to 4.3 years (median 2.1 years). In the placebo group, 37 developed recurrent venous thrombo-embolism (7.2 per 100 person-years) as compared with 14 in the low-intensity warfarin group (2.6 per 100 person-year) – a risk reduction of 64% (p<0.001). Major bleeding occurred in two patients in the placebo vs. five patients in the low intensity warfarin group (p=0.25). Low intensity warfarin was associated with a 48% reduction in the composite end point recurrent venous thrombo-embolism, major haemorrhage or death.
Preliminary data from Kearon et al shows that initial low-intensity warfarin (target INR 1.5-1.9) is significantly less effective than conventional-intensity warfarin (target INR 2.0-3.0) (4).
Therefore, it seems appropriate to wait for the publication of more trials. While waiting for such trials initial therapy with target INR 2.0-3.0 for at least 6 months followed by low intensity AC therapy might be an option in some patients. Also, new drugs like oral thrombin inhibitors should be tested in this setting.
1) Hull R, Hirsh J, Gent M et al. Different intensities of oral anti-coagulant therapy in the treatment of deep proximal-vein thrombosis. N Engl J Med 1982; 307: 1676-81.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6755255&dopt=Abstract
2) Hirsh J, Dalen JE, Anderson DR et al. Oral anticoagulants: mechanism of action, clinical effectiveness and optimal therapeutic range. Chest 2001; 119: Suppl:8S-21S.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11157640&dopt=Abstract
3) Ridker PM, Goldhaber SZ, Danielson E et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thrombo-embolism. N Engl J Med 2003; 348: 1425-34.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12601075&dopt=Abstract
4) Kearon C, Ginsberg JS, Kovacs M et al. Low-intensity (INR 1.5-1.9) versus conventional-intensity (INR 2.0-3.0) anticoagulation for extended treatment of unprovoked VTE: a randomized double blind trial. Blood 2002; 100: 150a (abstract).http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12565715&dopt=Abstract
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