Arixtra and Exanta herald a renaissance in the management of both venous and arterial disorders that feature thrombosis. In a related editorial published in the same issue, Shapiro said, “The authors of the three reports have been doing an outstanding service in bringing the potential of these agents to the attention of the medical community in a convincing manner. Nevertheless, a great deal remains to be learned regarding the place of the new drugs, used alone or in combination with antiplatelet agents, in the treatment of diseases associated with arterial thrombosis, particularly myocardial infarction and stroke…. It is likely that the first decade of the 21st century will continue to be a time of great advances in the treatment of thrombotic disorders.”

MATISSE

Buller led the MATISSE investigators in the publication of Subcutaneous Fondaparinux versus Intravenous Unfractionated Heparin in the Initial Treatment of Pulmonary Embolism. The researchers found that once-daily Arixtra, without monitoring, is at least as effective and is as safe as adjusted-dose, intravenous unfractionated heparin for the initial anticoagulation of hemodynamically stable patients with acute, symptomatic pulmonary embolism. They randomized 1,110 patients to receive unfractionated heparin and 1,103 to receive Arixtra.

During 3 months of follow-up, recurrent venous thromboembolism was diagnosed in 3.8% of patients in the Arixtra group and 5.0% in the unfractionated heparin group. The respective mortality rates were 5.2% and 4.4% (0.8% absolute difference, not statistically significant). The respective major or clinically relevant nonmajor bleeding rates were 4.5% and 6.3%. The noninferiority of Arixtra was demonstrated.

EXULT A

Francis led the EXULT A Study Group in the publication of Comparison of Ximelagatran with Warfarin for the Prevention of Venous Thromboembolism after Total Knee Replacement. Exanta is compared to the longstanding oral anticoagulant of choice, warfarin, for up to 12 days after total knee replacement surgery. 1,851 study subjects were randomized to receive either Exanta 36 mg twice daily, Exanta 24 mg twice daily, or a standard warfarin regimen.

Compared to warfarin, higher dose Exanta significantly reduced the risk of venous thromboembolism or death by nearly 27%. The risk reduction associated with the use of lower dose Exanta was almost 10%, but this difference was not statistically significant. Bleeding incidence for up to 2 days after the last dose of study drug was similar between groups.

THRIVE III

Schulman led THRIVE III Investigators in the publication of Secondary Prevention of Venous Thromboembolism with the Oral Direct Thrombin Inhibitor Ximelagatran. The group also assessed Exanta’s prophylactic effects, but this study focused on patients with venous thromboembolism who had already undergone anticoagulant treatment for 6 months.

Exanta’s effect at the level of risk of recurrence was clinically and statistically significant. Recurrence occurred for approximately 3% of Exanta recipients and 13% of placebo recipients (p < 0.001). The well-documented, transient increased incidence of elevated aminotransferase levels (a liver function test) in the Exanta group (cumulative risk 6.4% versus 1.2%, p < 0.001) was observed in this investigation. Resolution of the biochemical concern typically occurred within the first 4 months of use.

Exanta’s liver function concern will be sorted out in longer-term trials that will also seek to understand the longer-term consequences for direct thrombin inhibition.