Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis.

BACKGROUND: Although recombinant human soluble thrombomodulin (rhTM) is a widely used novel anticoagulant agent for disseminated intravascular coagulation (DIC) in Japan, its clinical efficacy in sepsis-induced DIC has not been demonstrated convincingly.

OBJECTIVE: To assess the benefits and harms of rhTM in sepsis-induced DIC patients.

METHODS: We conducted a systematic review and meta-analysis of rhTM therapy for sepsis-induced DIC for both randomized controlled trials (RCTs) and observational studies (retrospective case-control studies and/or prospective cohort studies) separately. All-cause mortality (28-30 days) as efficacy and serious bleeding complications as adverse effect were measured as primary outcomes. We assessed body of evidence quality at the outcome level by using the Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach.

RESULTS: We analyzed 12 studies (838 patients/3 RCTs; 571 patients/9 observational studies). Pooled relative risk was 0.81 (95% CI, 0.62-1.06) in the RCTs, indicating non-significant reduction in mortality, and 0.59 (95% CI, 0.45-0.77) in the observational studies. Meta-regression analysis revealed a significant negative slope between effect size of rhTM therapy and baseline mortality rate in individual studies (P = 0.012), suggesting that probability of a beneficial effect with rhTM therapy increases with increasing baseline risk. Risk of serious bleeding complications was not significantly different between rhTM and control groups. We judged the quality of evidence as moderate for mortality and serious bleeding.

CONCLUSIONS: The rhTM was associated with a trend in reduction of mortality at 28-30 days in sepsis-induced DIC patients. Further large rigorous trials are needed to confirm or refute these findings before implications for practice are clear.