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

Abstract

Objective: To evaluate the benefits and harms of antithrombin III in critically ill patients.

Design: Systematic review and meta-analysis of randomised trials.

Data sources: CENTRAL, Medline, Embase, International Web of Science, LILACS, the Chinese Biomedical Literature Database, and CINHAL (to November 2006); hand search of reference lists, contact with authors and experts, and search of registers of ongoing trials.

Review methods: Two reviewers independently selected parallel group randomised clinical trials comparing antithrombin with placebo or no intervention and extracted data related to study methods, interventions, outcomes, bias risk, and adverse events. Disagreements were resolved by discussion. Trials in any type of critically ill patients in intensive care were eligible. All trials, irrespective of blinding or language status, that compared any antithrombin III regimen with no intervention or placebo were included. Trials were considered to be at low risk of bias if they had adequate randomisation procedure, blinding, and used intention to treat analysis. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models according to heterogeneity.

Main outcome measures: Mortality, length of stay in intensive care or hospital, quality of life, severity of sepsis, respiratory failure, duration of mechanical ventilation, incidence of surgical intervention, intervention effect among various populations, and adverse events (such as bleeding).

Results: 20 trials randomly assigning 3458 patients met inclusion criteria. Eight trials had low risk of bias. Compared with placebo or no intervention, antithrombin III did not reduce overall mortality (relative risk 0.96, 95% confidence interval 0.89 to 1.03). No subgroup analyses on risk of bias, populations of patients, or with and without adjuvant heparin yielded significant results. Antithrombin III increased the risk of bleeding events (1.52, 1.30 to 1.78). Heterogeneity was observed in only a few analyses.

Conclusion: Antithrombin III cannot be recommended for critically ill patients based on the available evidence.

Fig 1 Identification of trials for inclusion

Fig 2 Forest plot of mortality (subgroup analyses on risk of bias). Weight is relative contribution of each study to overall estimate of treatment effect on log scale assuming random effects model

Fig 3 Forest plot for bleeding events

Fig 4 Forest plot of overall mortality based on heparin administration with fixed relative risk (Warren 2001w1 data split based on heparin administration)

Fig 5 Forest plot on overall mortality based on heparin administration, with random relative risk (Warren 2001w1 data split based on heparin administration)

Fig 6 Funnel plot

Fig 7 Trial sequential analysis (cumulative meta-analysis) assessing effect of antithrombin III in critically ill patients. Cumulative z curve (red dashed line) does not cross sequential monitoring boundary constructed for sample size of 3317 patients in meta-analysis (blue line) with relative risk reduction of 10% (from 48.5% to 43.2%) (α=0.05) and power of 80% (β=0.20). With total number of accrued participants in randomised trials being 3458, we can reject relative risk reduction of 10% at 80% power

Fig 8 Trial sequential analysis (cumulative meta-analysis) assessing effect of antithrombin III in critically ill patients with sample size adjusted for low bias heterogeneity. Cumulative z curve (red dashed line) does not cross trial sequential monitoring boundary (blue line) constructed for sample size of 14 294 patients, corresponding to relative risk reduction of 5% (from 48.5% to 46.2%) with α=0.05 and 80% power (β=0.20). Only 24% of required information size has been reached so far