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Objective: To assess the risks and benefits of oral anticoagulant treatment extended beyond 3 months after a first episode of deep vein thrombosis in patients who carry factor V Leiden mutation. Such patients have over twice the risk of recurrence after the recommended treatment period, but more information is required before widespread genetic screening can be recommended. Design: A decision analysis Markov model (with data extracted form literature) representing the risks of developing symptomatic venous thromboembolism, the risks of major bleeding, and the efficacy of anticoagulant treatment. Subjects: A hypothetical cohort of 1000 carriers of factor V Leiden recovering from a first episode of deep vein thrombosis in the lower limbs. Main outcome measures: Risks and benefits of, firstly, stopping oral anticoagulation 3 months after first episode of thrombosis with reinitiation of treatment only after recurrent thrombosis and, secondly, extension of oral anticoagulation up to 1 to 5 years. Results: Despite consistent biases in favour of extended oral anticoagulation, analysis revealed that among factor V carriers the number of major haemorrhages induced by oral anticoagulants would exceed that of clinical pulmonary emboli prevented over the entire range of duration of anticoagulation (1 to 5 years). On the other hand, the number of recurrent deep vein thrombi prevented would exceed that of iatrogenic major bleedings. Conclusion: The lack of evidence of a net clinical benefit of prolonged oral anticoagulation, at least beyond 1 year, among patients recovering from acute deep vein thrombosis does not support the decision to promote widespread genetic screening programmes to detect the factor V mutation.
A point mutation in which adenine is substituted for guanine at nucleotide 1691 in the gene coding for coagulation factor V results in the production of abnormal factor V (called factor V Leiden) which is more resistant to inhibition by activated protein C than the genuine factor V. This mutation is associated with a threefold to sevenfold increase in the risk of deep vein thrombosis. Because its prevalence is quite high in Western populations (about 5% in Europe with a maximum of 15% in southern Sweden), there is a large debate among specialists as to whether genetic screening is indicated.
Before screening for any abnormality is advocated in more or less selected groups of symptomatic or asymptomatic patients, however, data should demonstrate that carriers of the mutation would benefit from the diagnosis. For example, women who carry the factor V Leiden mutation and use oral contraceptives have a more than 30-fold increased risk of thrombosis compared with women who are not carriers of the mutation and do not use oral contraceptives; screening for the mutation, however, would deny effective contraception to a large number of women while preventing only a small number of deaths due to pulmonary emboli. Similarly, the finding that factor V Leiden mutation is associated with a twofold risk of recurrent thrombosis,[8 9] a finding that has recently been challenged, does not necessarily mean that patients who carry the mutation and present with acute deep vein thrombosis would benefit from more prolonged anticoagulation (some specialists advocate indefinite treatment) to prevent recurrent disease. This policy would imply the need for secondary screening programmes with factor V Leiden testing in all patients experiencing deep vein thrombosis. Ideally, the answer to that question should be derived from randomised trials comparing long term (but how long?) versus short term anticoagulation with adjusted dose oral anticoagulants in the secondary prevention of venous thromboembolism among patients heterozygous for factor V Leiden. Such trials with sufficiently large numbers of patients would be difficult to organise and their results would probably not be available for many months or even years. This prompted us to use a Markov decision analysis model explicitly considering the consequences of recurrent deep vein thrombosis and bleeding events and to quantify the risk-benefit trade offs for different durations of oral anticoagulant treatment in these patients at higher risk of recurrent thromboembolic events.
This kind of approach is particularly suited for assessing complex clinical issues by using the best available evidence from the literature. Moreover, sensitivity analyses allow one …