Antithrombin III for critically ill patients: a systematic review with meta-analysis and trial sequential analysis

Abstract

Purpose: Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties. We assessed the benefits and harms of AT III in critically ill patients.

Methods: We searched from inception to 27 August 2015 in CENTRAL, MEDLINE, EMBASE, CAB, BIOSIS and CINAHL. We included randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status, outcomes published or language.

Results: We included 30 RCTs with a total of 3933 participants. The majority of included trials were at high risk of bias. Combining all trials, regardless of bias, showed no statistically significant effect of AT III on mortality (RR 0.95, 95% CI 0.88-1.03, I (2) = 0%, fixed-effect model, 29 trials, 3882 participants). Among those with severe sepsis and disseminated intravascular coagulation (DIC), AT III showed no impact on mortality (RR 0.95, 95% Cl 0.88-1.03, I (2) = 0%, fixed-effect model, 12 trials, 2858 participants). We carried out multiple subgroup and sensitivity analyses to assess the benefits and harms of AT III and to examine the impact of risk of bias. AT III significantly increased bleeding events (RR 1.58, 95% CI 1.35-1.84, I (2) = 0%, fixed-effect model, 11 trials, 3019 participants). However, for all other outcome measures and analyses, the results did not reach statistical significance.

Conclusions: There is insufficient evidence to support AT III substitution in any category of critically ill participants including those with sepsis and DIC. AT III did not show an impact on mortality, but increased the risk of bleeding.

Keywords: Antithrombin III; Bleeding; DIC; Multi organ failure; Sepsis; Septic shock.

Fig. 1

Flow chart in accordance with The Cochrane Collaboration guidelines. Three authors (FR, MA and AA) independently examined all potential primary studies and decided on their inclusion in the review

Fig. 2

Risk of bias summary. All trials were evaluated for major potential sources across the various bias domains in accordance with The Cochrane Collaboration’s tool for risk of bias assessment

Fig. 3

Forest plot of overall mortality with subgroup analysis based on the overall methodological quality of the included trials (trials with low risk of bias versus trials with high risk of bias). CI confidence interval, M–H Mantel–Haenszel

Fig. 4

Forest plot of overall mortality among patients with severe sepsis and disseminated intravascular coagulation (DIC) with subgroup analysis based on the overall methodological quality of the included trials (trials with low risk of bias versus trials with high risk of bias). CI confidence interval, M–H Mantel–Haenszel

Fig. 5

Trial sequential analysis (TSA) of all trials of the effect of AT III on mortality. Cumulative Z curve in blue does not cross the boundary constructed for an information size of 5037 in the meta-analysis (full red line with diamonds) with a relative risk reduction (RRR) of 10 % (α = 0.05) and a power of 80 % (β = 0.20). However, the cumulative Z curve breaks through the boundary for futility (non-superiority). The analysis therefor led to rejection of an intervention effect of an RRR of 10 % with a power of 80 % in 30 randomized trials with a total number of accrued participants of 3882