The traditional treatment of thromboembolic disease is based on warfarin and unfractioned heparin or low molecular weight heparin or fondaparinux, which have many difficulties in their usage. In recent years there were a number of clinical trials that aimed at improving anticoagulant therapy and patient’s quality of life. New anticoagulants are directed on specific targets (single factors) of the coagulation cascade. Rivaroxaban is an oral, direct, specific and reversible factor Xa-inhibitor. Rivaroxaban is presently studied in many clinical trials, some of which are still ongoing. “EINSTEIN” is a phase III, randomized, open-label, non inferiority study which evaluates whether Rivaroxaban is at least as effective as traditional therapy in the treatment of patients with thromboembolic disease and for secondary prevention of recurrent venous thromboembolic events. In the “EINSTEIN” protocol two groups of patients are integrated: “EINSTEIN DVT”, which includes patients with confirmed acute symptomatic deep venous thrombosis (DVT) without symptomatic pulmonary embolism (PE) and “EINSTEIN PE”, which includes patients with confirmed acute symptomatic PE with or without symptomatic DVT. The two groups are submitted to the same therapeutic strategy, in terms of dosages and duration. Patients randomized to receive Rivaroxaban are treated with an initial dosage of Rivaroxaban 15 mg twice daily for three weeks, and subsequently with Rivaroxaban 20 mg once daily to complete three, six or twelve months of treatment. This treatment is compared with the traditional treatment including enoxaparin 1.0 mg/100 U.I/Kg twice daily, followed by vitamin K antagonist adjusted to target International Normalized Ratio (INR) of 2.5. The “EINSTEIN” study started on 2007 and involves 300 sites worldwide. Italy participates with 14 active sites. The “EINSTEIN” study will be completed in February 2010.

BACKGROUND AND OBJECTIVES:Delayed thrombus regression after a first episode of deep vein thrombosis (DVT) of the inferior limbs has been implicated in the development of the post-thrombotic syndrome. Whether normalization of vein segments involved in the index DVT has prognostic significance with respect to the probability of DVT recurrence or new thrombosis is currently unknown. In this study, we prospectively monitored thrombus regression in consecutive patients with symptomatic and asymptomatic DVT. Factors affecting normalization rates and the relationship between previous normalization and DVT recurrence or new thrombosis were explored. DESIGN AND METHODS:One hundred and seventy-nine patients with a first episode of symptomatic DVT of the lower limbs (38 with cancer) and 104 patients with DVT occurring after hip replacement surgery were serially monitored by real time B-mode compression ultrasonography (C-US) over a period of 12 months (months 1, 3, 6 and 12). C-US normalization of popliteal and femoral venous segments was arbitrarily assigned to be residual thrombus occupying, at maximum compressibility, less than 40% of the vein area in the absence of compression. RESULTS:In patients with no DVT recurrence or new thrombosis, C-US normalization was observed at 12 months in 100% of 99 patients with post-operative DVT, in 59% of 134 cancer-free symptomatic DVT outpatients and in 23.3% of 30 symptomatic DVT outpatients with cancer (p = 0.0001). Independent negative effects on the probability of C-US normalization were observed for younger age (p <0.05), for the outpatient presentation of the index DVT (p 0.017), for DVT involving the entire femoro-popliteal axis (p 0.05), and for the presence of cancer (p 0.05). DVT recurrence or new thrombosis was observed in 5 patients with post-operative DVT (4.8%), in 7 cancer-free patients with symptomatic DVT (5.0%) and in 8 patients with cancer (21.1%). Only 4 of these patients had shown normalization of their index DVT prior to the event. The presence of cancer was the only significant predictor of DVT recurrence and/or new thrombosis occurring within 3 months from the index DVT (OR = 4.90, p = 0.002). The absence of previous C-US normalization was the only predictor of recurrence or new thrombosis occurring after 3 and 6 months from the index DVT (OR 5.26, p 0.027). INTERPRETATION AND CONCLUSIONS:Absence of C-US normalization after a first episode of DVT appears to be a factor favoring recurrence or new thrombosis and may be relevant to the optimal duration of oral anticoagulant treatment.

Background-Patients with venous thromboembolism require initial treatment with an immediate-acting anticoagulant, low-molecular-weight heparin. We evaluated a novel synthetic factor Xa inhibitor (SR90107a/ORG31540) as an alternative treatment.Methods and Results-A randomized-parallel-group, phase II trial to assess the efficacy and safety of SR90107a/ORG31540 (5, 7.5, or 10 mg once daily) relative to low-molecular-weight heparin (dalteparin, 100 IU/kg twice daily) in symptomatic proximal deep vein thrombosis. The primary outcome measure was the change in thrombus mass, assessed by ultrasonography of the leg veins and perfusion lung scintigraphy, performed at baseline and day 7+/-1. A positive outcome was defined as improvement of the ultrasound and/or perfusion scan result without deterioration of either test. Other outcome measures included symptomatic, recurrent venous thromboembolism and major bleeding for a period of 3 months. All outcomes were interpreted with the observer unaware of treatment allocation. A positive primary outcome was observed in 46 of 100 (46%), 52 of 108 (48%), 48 of 115 (42%), and 56 of 115 (49%), respectively, of the subjects given 5, 7.5, or 10 mg SR90107a/ORG31540 or dalteparin. There were 8 recurrent thromboembolic complications (2.4%) in the 334 patients treated with SR90107a/ORG31540 and 6 (5.0%) in the 119 dalteparin patients, a difference of 2.6% in favor of SR90107a/ORG31540 (95% CI -2.1% to 10.1%). The incidence of bleeding was low and was similar among the groups.Conclusions-The factor Xa inhibitor SR90107a/ORG31540 appears to be an effective and safe treatment for patients with deep vein thrombosis across a wide range of doses. This synthetic compound merits evaluation in phase III studies.

Low molecular weight heparins (LMWHs) are commonly employed as a substitute for unfractionated heparin (UFH) in the treatment of venous thromboembolic events. Despite their higher cost, the preferential use of LMWHs seemed justified initially as, based on the results of earlier meta-analyses, these compounds were deemed to be more effective and safer than UFH. Although, in this respect, their purported superiority over UFH could not be confirmed by subsequent large, randomised trials and updated meta-analyses, other peculiar features of LMWHs were highlighted, favouring their preferential utilisation in patients with venous thromboembolism. Among these, the possibility of once-daily administration on an out-patient basis, the lower incidence of Type II heparin-induced thrombocytopenia and the lower likelihood of osteoporosis after prolonged treatment periods, appear to be especially prominent. This review attempts to evaluate the available evidence focusing on the safety of LMWHs for the treatment of venous thromboembolism and the current therapeutic options and potential advantages of LMWHs, either in general or in selected patient populations.