Treatment effects of high‐dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation

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 ¼ 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P ¼ 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 ¼ 0.6; 9.8% vs. 3.1% for patients without DIC, P ¼ 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 highdose AT treatment.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J‐SSCG2016)

“…The KyberSept trial390 assessed severe sepsis rather than sepsis‐associated DIC, and so could not be adopted as evidence for this CQ, as it does not consider treatments for sepsis patients without DIC. Thus a post‐hoc analysis in a study by Kienast et al .,402 which was limited to sepsis‐associated DIC, was adopted. Meanwhile, the efficacy and risks of the dosage covered by the National Health Insurance for the intervention itself (1,500 units/day for patients with sepsis‐associated DIC with antithrombin activity levels of 70% or lower, and 40–60 units/kg in surgical cases) were also assessed.…”

“…In addition, four Japanese and overseas studies395, 402, 403, 404 were analyzed. The treatment intervention was expected to be beneficial in terms of reduced mortality rate based on an RR of 0.68 (95% CI: 0.49–0.93), but bias risk/indirectness may lower the reliability of the effect estimate.…”

A summary of the Japan septic disseminated intravascular coagulation study

“…However, the post‐hoc subgroup analyses of those RCTs indicated that the anticoagulant therapies resulted in improved mortality rates in patients with sepsis‐induced DIC 8, 9. In Japan, anticoagulant therapy has been approved for use as adjunctive therapy for patients with sepsis‐induced DIC and is now widely applied in clinical settings.…”

Thrombin physiology and pathophysiology

“…64 There have been some sepsis studies that demonstrate improved survival in patients whose AT activity is enhanced with high dose AT therapy instead of heparin administration. 65 Newer anticoagulant drugs are designed around several mechanisms: (1) preventing the initiation of coagulation, (2) decreasing thrombin generation, and (3) directly inhibiting thrombin interactions. Newer pharmaceuticals designed to block the initiation of coagulation include tifacogin and NAPc2.…”