Abstract and Introduction
Abstract
Objectives: To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation.
Design: Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial.
Setting: Two hundred and thirty-three ICUs in 17 countries.
Patients: All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score.
Interventions: Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity.
Measurements and Main Results: A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran–Mantel–Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline.
Conclusions: ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.
Introduction
Severe sepsis remains the most common cause of death in critically ill patients, and new therapeutic approaches are urgently needed. Disseminated intravascular coagulation (DIC), resulting from widespread intravascular activation of coagulation pathways and diagnosed based on laboratory evidence of consumption of clotting factors and platelets and of fibrin cleavage, may occur in a range of medical conditions including trauma, burns, obstetric emergencies, and malignancies. DIC is also a frequent complication of severe sepsis, and when present it is associated with increased mortality in these patients.
Current management of DIC is primarily focused on treating any associated underlying medical condition, although use of supplemental clotting factors or platelets, or anticoagulant therapy may occasionally be required. ART-123 (Artisan Pharma, Waltham, MA) is a soluble recombinant human thrombomodulin that acts by reducing thrombin-mediated clotting and enhancing protein C activation at the site of clotting. ART-123 also has anti-inflammatory properties, including interfering with the activation of complement and inactivating high-mobility group protein B1, a mediator associated with mortality in late sepsis. IV injection of ART-123 appears to enhance the reversal of DIC in patients with infection or hematologic malignancy and may reduce organ dysfunction and mortality in patients with sepsis-associated DIC.
On the basis of a potential benefit of ART-123 in sepsis-induced DIC and in the absence of previous randomized studies in this population, we sought to determine the safety and efficacy of ART-123 when combined with standard care in patients with sepsis-associated DIC.