Current treatment for acute venous thromboembolism (VTE) consists of an initial course of subcutaneous low-molecular-weight heparin or intravenous unfractionated heparin given for at least 5 days, followed by oral vitamin K antagonists given for a minimum of 3 months [1]. This long-term treatment with adjusted doses of vitamin K antagonists [International Normalized Ratio (INR) 2.0–3.0] is highly effective in preventing recurrent episodes of VTE for as long as it is continued. The results of four studies, that excluded patients with known cancer, indicate that during anticoagulant treatment the rate of VTE recurrence is lower than 1% per year [2-5]. However, after discontinuation of anticoagulant treatment, patients with idiopathic or unprovoked VTE have a high risk of recurrence (approximately 5% per year over the next 2 or 3 years), indicating that the benefit for reducing recurrent VTE is not maintained after vitamin K antagonists have been discontinued [4, 5]. This is probably because patients with idiopathic or unprovoked VTE are chronically exposed to one or more underlying genetic or acquired predisposing factors for VTE [6]. The high rate of VTE recurrence seen in patients with idiopathic VTE after discontinuation of vitamin K antagonists suggests the need for extended anticoagulant treatment and makes the strategy that was assessed in the PREVENT study an issue of particular interest. The Prevention of Recurrent Venous Thromboembolism (PREVENT) study tested the hypothesis that extended treatment with low-intensity warfarin therapy (target INR 1.5–2.0) could provide a safe and effective method of reducing the risk of recurrent VTE in patients with idiopathic VTE [7]. After completing a period of at least 3 months of standard-intensity therapy with vitamin K antagonists (target INR 2.0–3.0), 508 patients with deep vein thrombosis (DVT) or pulmonary embolism were randomly allocated to receive low-intensity warfarin therapy or placebo in a double-blinded fashion. The trial was terminated after a mean study period of 2.1 years because there was strong evidence for the superiority of low-intensity warfarin therapy over placebo. The results of the study showed a relative risk reduction of 64% in favor of warfarin (7.2 per 100 patient-years in the control group compared with 2.6 per 100 patient-years in the warfarin group) and an absolute risk reduction of 4.6%, equivalent to one event prevented for every 22 patients treated for 1 year. All subgroups had a benefit from low-intensity warfarin therapy, including patients with factor (F)V Leiden or prothrombin gene mutation, patients with first-time VTE or recurrent VTE, and young or old patients. To assess the clinical relevance of the results of the PREVENT study the following issues should be considered: the efficacy and safety of low-intensity warfarin therapy in comparison with other therapeutic strategies, the issue of treatment practicality and the actual and potential room for alternative strategies for the prevention of recurrence of VTE. The results of the PREVENT study should be interpreted in the light of the recently reported head-to-head comparison between low-intensity warfarin therapy (target INR 1.5–1.9) and standard-intensity therapy (INR 2.0–3.0) for the extended treatment of idiopathic or unprovoked VTE [8]. In this randomized double-blind study all patients had completed at least 3 months of standard-intensity warfarin therapy before randomization. After an average follow-up was 2.3 years, the incidence of recurrent VTE was 1.9% per year among the 370 patients in the low-intensity group and 0.6% per year among the 369 patients in the standard-intensity group [hazard ratio (HR) 3.3, 95% confidence interval (CI) 1.2, 9.1, absolute risk increase of 1.3% per patient-year, equivalent to one event caused for every 77 patients treated for 1 year). Thus, this study showed that low-intensity warfarin therapy is less effective than standard-intensity therapy in the prevention of VTE recurrences after a period of standard-intensity therapy of at least 3 months' duration. In patients with VTE the benefit from extended treatment with vitamin K antagonists may be offset by the risk of bleeding. Standard-intensity therapy with warfarin is associated with an incidence of 0.2–0.6% per year of fatal bleeding, 2–3% of major bleeding and 5–15% of minor bleeding. Therefore, anticoagulant treatment regimens that promise a more favorable benefit-to-bleeding ratio, such as low-intensity oral anticoagulation therapy, are extremely appealing. Does the PREVENT study provide a strategy to improve the safety of oral anticoagulation? In this study bleeding episodes requiring hospitalization occurred in two patients in the placebo group (0.4 per 100 person-years) and five patients in the low-intensity oral anticoagulation group (0.9 per 100 person-years). Although the PREVENT trial showed no significant excess of major bleeding with low-intensity warfarin therapy compared with placebo, event rates were low and the 95% CIs do not reliably exclude even a 13-fold increase in risk of major bleeding (HR 2.53; 95% CI 0.49, 13.03) [9]. In the PREVENT trial, minor bleeding was significantly increased in the low-intensity oral anticoagulation group compared with the placebo group (12.8% vs. 6.7%; HR 1.92; 95% CI 1.26, 2.93) with an increase in absolute risk of 6.1%, equivalent to one minor bleed caused for every 16 patients treated for 1 year. In the head-to-head comparison between low-intensity warfarin therapy and standard-intensity therapy the incidence of major bleeding was 1.0% per year in the low-intensity group and 0.9% per year in the standard-intensity group (HR 1.0; 95% CI 0.4, 2.7) [8]. The corresponding incidences of all bleeding (major and minor) were 4.9% per year and 3.6% per year, respectively (HR 1.3; 95% CI 0.8, 2.1). It has been observed that in this study the rate of bleeding complications was lower than that seen in previous trials on oral anticoagulation for idiopathic VTE (approximately 3% per year). It could not be excluded that patients at increased risk of bleeding were excluded from Kearon's study, so reducing the likelihood of low-intensity warfarin therapy showing a safer profile than standard-intensity therapy. However, the low bleeding rate observed in this study during the extended anticoagulation treatment is similar to the rate observed in other studies with a similar experimental design [5]. It is likely that in the extended period following the first 3–6 months of anticoagulation the bleeding risk decreases over time, so making the standard-intensity therapy less frequently associated with major bleeding and more affordable for the patients. In the PREVENT study patients assigned to low-intensity warfarin required routine blood testing only once every 2 months. This reduced rate of INR controls may be an advantage in terms of treatment practicality. However, the low-intensity warfarin strategy does not eliminate all the drawbacks of the vitamin antagonists. Therefore, low-intensity warfarin therapy is unlikely to offer a significant advantage over standard-intensity therapy in terms of patient convenience. In patients with idiopathic or unprovoked VTE, at the end of treatment with oral anticoagulants (6 months to 1 year), clinicians have to make the decision whether to withdraw or continue this treatment. As alternatives to this dichotomic choice, two alternative strategies for the prevention of recurrent VTE are currently emerging: the identification of patients at high risk of recurrence in whom the extended treatment with vitamin K antagonists could be of greater benefit, and the implementation of alternative treatments as effective and safe as warfarin but with improved practicality. The first of these strategies would reduce the number of patients exposed to vitamin K antagonists, while the second would make extended treatment more feasible and more accepted by the patients. A variety of prothrombotic conditions or markers have been reported to be associated with an increased risk of recurrent VTE after withdrawal of vitamin K antagonists. These include deficiencies of the naturally occurring inhibitors of coagulation, specific gene mutations including FV Leiden and prothrombin 20210A, elevated levels of coagulation factor VIII and homocysteine, and the presence of antiphospholipid antibodies. More recently, the presence of residual DVT assessed by compression ultrasonography [10], and the presence of elevated plasma d-dimer levels after discontinuing anticoagulant therapy [11], have been associated with an increased incidence of recurrent VTE. No randomized trials have evaluated whether these predictors of VTE recurrence could be used in patient management. However, this approach appears quite attractive given the reported high negative predictive value of these tests for recurrence that it carries the advantage of the reduction in the number of patients requiring extended anticoagulation. In recent years a number of oral agents that do not require laboratory monitoring have entered clinical development. Among these the oral selective antithrombin agent ximelagatran has been evaluated in the long-term treatment of DVT. In the Thrive III study, following cessation of a standard 6-month period of treatment with warfarin, extended treatment with ximelagatran for 18 months was more effective than placebo in the prevention of recurrent VTE [12]. Ximelagatran was given without any coagulation monitoring. This observation highlights the wide therapeutic window of ximelagatran that allows for a fixed dosing regimen without monitoring and results in an increased practicality. Furthermore, the recently reported high incidence of acute myocardial infarction and ischemic stroke in patients with idiopathic or unprovoked pulmonary embolism re-opened the case for extended treatment with antiplatelet agents after a standard treatment with oral anticoagulants [12]. Two studies are currently exploring the hypothesis that aspirin could reduce the incidence of cardiovascular events in patients with idiopathic or unprovoked VTE after a standard treatment with oral anticoagulants. Based on the available evidence, when assessed after 3–6 months of standard anticoagulation, standard-intensity therapy with warfarin is more effective for preventing recurrent VTE than low-intensity warfarin therapy, which, in turn, is more effective than placebo. Low-intensity warfarin therapy has not been demonstrated to be safer than standard-intensity therapy in terms of bleeding and still requires close laboratory monitoring. If extended treatment beyond 3–6 months is required, standard-intensity therapy with oral anticoagulants (target INR 2.0–3.0) remains the treatment of choice in patients with idiopathic or unprovoked VTE and without risk factors for hemorrhagic complications. Alternative strategies with new anticoagulants that do not require monitoring will be available soon and, if their safety is confirmed, these agents will be valid candidates to replace vitamin K in the treatment of VTE. The hypothesis that antiplatelet agents could provide a more comprehensive cardiovascular protection in the extended treatment of patients with idiopathic VTE deserves to be tested.