Preclinical distorts the bleeding risk. Here are some key points from that study.
The article from Jan 2006 in J Thrombosis and Haemostasis 4:90-97.
Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation
Efficacy of AT treatment in sepsis patients with DIC
The treatment effect of high-dose AT without concomitant heparin on all-cause mortality of patients presenting with severe sepsis and DIC is shown in Fig. 1 and Table 2. In DIC patients, Kaplan–Meier survival functions until day 90 were significantly different between AT and placebo groups (P = 0.007; Fig. 1A), whereas no effect of high-dose AT on survival was seen in patients without DIC (P > 0.2; Fig. 1B).
Patients with overt DIC (n = 42) who received high-dose AT without concomitant heparin were found to have a trend towards a reduced mortality rate at 28 days compared with placebo patients: four of 20 (20.0%) vs. eight of 22 (36.4%), respectively [0.55 (0.20–1.55), P > 0.2]; at 90 days, mortality rates were six of 20 (30.0%) with AT and nine of 22 (40.9%) with placebo [0.73 (0.32–1.69), P > 0.2].
For patients who met the criteria for non-overt DIC (n = 223), both, the 28- and the 90-day mortality rates were significantly reduced in the AT group with a > 30% relative risk reduction compared with placebo. At 28 days, 29 of 113 (25.7%) of the AT patients not receiving concomitant heparin had died in contrast to 45 of 110 (40.9%) of the placebo patients [0.63 (0.43–0.92), P = 0.023]. At 90 days, the absolute treatment effect was even stronger with a mortality rate of 37 of 107 (34.6%) for the AT group and 57 of 110 (51.8%) for the placebo group [0.67 (0.49–0.92), P = 0.014].
Safety of AT and no heparin in DIC
Major bleeding rates were analyzed for the study drug infusion period (4 days) plus 24 postinfusion days. In patients without DIC at baseline, AT treatment was associated with a significant increase in the risk of major bleeding (9.8%) compared with a rate of 3.1% (P < 0.05) in placebo-treated patients (Table 3). Remarkably, in patients with DIC at baseline, the major bleeding rate was 7.0% in AT patients and did not significantly differ from the major bleeding risk (5.2%) found in the placebo patients (Table 3). The odds of major bleeding were not significantly different between patients with or without DIC in the AT treatment group (Breslow–Day interaction test, P = 0.23).
Abstract
Summary. Background: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality. Objectives: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC. Patients and Methods: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination. Results: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02). Conclusions: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment.
