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Ximelagatran prevented secondary venous thromboembolism
  1. Paolo Prandoni, MD
  1. University of Padua, Padua, Italy

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 Q What is the long term efficacy and safety of ximelagatran after 6 months of standard anticoagulant therapy for secondary prevention of venous thromboembolism (VTE)?

    Clinical impact ratings GP/FP/Primary care ★★★★★☆☆ IM/Ambulatory care ★★★★★★☆ Haematology ★★★★★★★


    Embedded ImageDesign:

    randomised placebo controlled trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE III]).

    Embedded ImageAllocation:


    Embedded ImageBlinding:

    blinded (clinicians, patients, {data collectors, outcome assessors, and data analysts}).*

    Embedded ImageFollow up period:

    18 months.

    Embedded ImageSetting

    142 centres in 18 countries.

    Embedded ImagePatients

    1233 patients who were ⩾18 years of age with symptomatic, objectively confirmed deep venous thrombosis (DVT) or pulmonary embolism (PE) and had received anticoagulant therapy for 6 months with no recurrent VTE event. Exclusion criteria: indication for continuous anticoagulant therapy, haemoglobin level <9.0 g/dl, platelet count <90 000/mm3, pregnancy, lactation, expected survival <18 months, renal impairment, clinically important liver disease, or persistent elevation of the aminotransferase level >3 times the upper limit of normal.

    Embedded ImageIntervention:

    twice daily ximelagatran, 24 mg (n = 612), or placebo (n = 611) for 18 months. All patients discontinued anticoagulant therapy but did not begin study treatment until the international normalised ratio (INR) was <1.5.

    Embedded ImageOutcomes:

    VTE (recurrent DVT and PE), major and minor bleeding, and all cause mortality.

    Embedded ImagePatient follow up:

    1223 patients (99%) (mean age 57 y, 53% men) were included in the intention to treat analysis.


    Fewer patients who received ximelagatran had recurrent VTE events than did patients who received placebo (table). Groups did not differ for major or minor bleeding or for all cause mortality (table).

    Ximelagatran v placebo for secondary prevention of venous thromboembolism (VTE) at 18 months*


    In patients with deep venous thrombosis or pulmonary embolism receiving standard anticoagulant therapy for 6 months, ximelagatran reduced recurrent venous thromboembolism and did not increase bleeding.

    Abstract and commentary also appear in ACP Journal Club.


    The trial by Francis et al shows the superiority of 36 mg twice daily of ximelagatran over warfarin, both started after surgery, for prevention of VTE after total knee replacement surgery. However, as the greater efficacy came entirely from a decreased incidence of isolated (largely asymptomatic) calf vein thrombosis, the interpretation of these results deserves comment.

    In most studies, comparing low molecular weight heparins (LMWHs), which have a rapid onset of action, and oral anticoagulants, which require 2–4 days to render an anticoagulant effect, the latter category of drugs has been less effective. Because both the study and the comparator drugs were started at the same time after surgery, I wonder whether the superiority of ximelagatran simply reflects the different onset of action of the 2 drugs. All that oral anticoagulants can do in this setting is prevent thrombus from growing. Indeed, both in this trial and in virtually all those assessing LMWHs, the incidence of proximal vein thrombosis and that of PE, when taken together, did not differ between patients receiving oral anticoagulants and those receiving heparin.

    Despite this consideration, warfarin is problematic for VTE prophylaxis because of the need for laboratory monitoring and potential drug interactions, and LMWHs are the standard of care for the prevention of VTE after orthopaedic surgery. Although ximelagatran was shown to be more effective than enoxaparin in the EXPRESS study,1 it has not been compared with fondaparinux, a synthetic anti-Xa inhibitor that is more effective than enoxaparin for VTE prophylaxis after orthopaedic surgery. The ultimate comparison of efficacy in the prevention of VTE after orthopaedic surgery may be a head to head comparison between ximelagatran and fondaparinux.

    The optimal long term treatment of patients who present with unprovoked (or idiopathic) VTE is controversial. 15%–30% of patients with idiopathic VTE will have recurrent VTE in the first year after 3–6 months of anticoagulation. Prolonging the duration of anticoagulation beyond 3–6 months may delay recurrences while exposing patients to the haemorrhagic risk associated with extended anticoagulation. The possibility that a lower intensity warfarin regimen (INR 1.5–1.9) would allow safer anticoagulation without compromising efficacy2 was trumped by the results of another study that showed that conventional intensity anticoagulation (INR 2.0–3.0) has better efficacy than a lower intensity regimen.3 The results of the trial by Schulman et al show that long term ximelagatran therapy, administered orally in a fixed dose and without laboratory monitoring, is effective for preventing recurrent VTE in patients who received 6 months of conventional anticoagulant therapy and is not associated with an increased haemorrhagic risk.

    However, the extent to which ximelagatran prevented recurrent VTE was not different from that of oral anticoagulants in the many trials that addressed their benefit. Furthermore, the apparent lack of haemorrhagic potential may have been because of the unusually high rate of bleeding in patients who received placebo. Finally, in about 6% of patients, aminotransferase concentrations increased to >3 times the upper limit of normal. Additional research is required to identify the optimal strategy of long term anticoagulation in patients with idiopathic VTE. There is the potential that disease recurrence can be predicted on an individual basis after 3–6 months of conventional therapy if venous ultrasonography shows persistent abnormalities or D dimer levels are elevated.4,5


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    • * See glossary.

    • Information provided by author.

    • For correspondence: Dr S Schulman, Karolinska Hospital, Stockholm, Sweden.

    • Source of funding: AstraZeneca Research and Development.