I would say the phase III data was interesting but the mortality rates didn't
to appear to improve as much as it did with rATIII. ART showed a 6.6% decrease over heparin. Off hand, I recall the rATIII trial was against placebo. Below is some data from the article you cited.
<<Non-significant trends in favor of ART-123, as compared with heparin, were observed for mortality in patients with DIC associated with infection. The mortality rate for the ART-123 group was 6.6% lower than that for the heparin group [reduction in relative risk of death (rrr) = 19.1%]. In the PROWESS trial on severe sepsis, recombinant APC was shown to reduce the mortality rate by 6.1% as compared with placebo (P = 0.005, rrr = 19.4%) [25]. In fact, APC is the only drug for which an effect on mortality in sepsis has been demonstrated against placebo, in spite of many methodological concerns [26]. In contrast to the very short in vivo half-life of recombinant APC, ART-123 has a long in vivo half-life, and also has a unique N-terminal structure that exhibits anti-inflammatory activity [27]. ART-123 might be appropriate for septic patients with reduced endothelial thrombomodulin [28]. It would be interesting to investigate whether ART-123 would significantly reduce the mortality rate in a large-scale clinical study, as compared with placebo, in patients with DIC secondary to infection or sepsis.
Like numerous previous studies [29–32], we found that DIC is a strong predictor of mortality in patients with DIC associated with infection. For patients with resolved DIC (no DIC), 28-day mortality for the ART-123 and heparin groups was 3.1% (1/32 patients) and 17.9% (5/28 patients). For patients without resolved DIC, 28-day mortality for the ART-123 and heparin groups was 68.8% (11/16 patients) and 52.2% (12/23 patients). For both drug groups, patients with resolved DIC had a lower mortality rate.
Because the diagnostic criteria for overt DIC recently proposed by the International Society on Thrombosis and Haemostasis (ISTH DIC criteria) [33] were not yet available at the start of this study, we utilized the JMHW DIC criteria [19], which have been widely used in clinical settings in Japan. The ISTH DIC criteria are based, in principle, on the JMHW DIC criteria for patients without blood disease, and both criteria are reported to be similarly effective in identifying DIC patients [34,35]. The validity of the ISTH scoring system in critical care settings excluding 'hematologic malignancy' has been proved against 'expert opinion' [36]. By using the same approach, the sensitivity and specificity of the JMHW scoring system for patients with severe thrombocytopenia have been validated in leukemia-associated DIC [37]. It was shown that the JMHW scoring system is superior to the ISTH scoring system in terms of sensitivity and negative predictive value for leukemia-associated DIC. Thus, it appears that both JMHW scoring systems with or without severe thrombocytopenia are comparable in the diagnosis of DIC. In the protocol of this study, we prospectively defined a combined analysis of DIC resolution rate. Therefore, a combined analysis of data from hematologic malignancy and infection may be justified.
Here, we have demonstrated the superiority of ART-123 as a drug for the treatment of DIC over low-dose heparin. Because of its safety and efficacy, ART-123 appears to be a promising agent in the treatment of DIC associated with hematologic malignancy or infection and in the prevention of venous thromboembolism [38]. It is likely that ART-123 may be efficacious for the treatment of patients with DIC associated with solid tumor, pediatric DIC patients or obstetric DIC patients. In addition, previous studies have shown that thrombomodulin plays a central role in regulating not only hemostasis but also inflammation, and that ART-123 also possesses both antithrombotic and anti-inflammatory activities [27,39,40]. Therefore, ART-123 may be useful in the management of various diseases that are exacerbated by inflammation–coagulation interactions, such as sepsis, acute respiratory distress syndrome and inflammatory bowel disease. Further clinical investigations are necessary to clarify this point.>>
