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Meta-Analysis
. 2016 Feb 8;2(2):CD005370.
doi: 10.1002/14651858.CD005370.pub3.

Antithrombin III for critically ill patients

Mikkel Allingstrup  1 , Jørn Wetterslev, Frederikke B Ravn, Ann Merete Møller, Arash Afshari
Affiliations
Meta-Analysis

Antithrombin III for critically ill patients

Mikkel Allingstrup et al. Cochrane Database Syst Rev. .

Abstract

Background: Critical illness is associated with uncontrolled inflammation and vascular damage which can result in multiple organ failure and death. Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties but the efficacy and any harmful effects of AT III supplementation in critically ill patients are unknown. This review was published in 2008 and updated in 2015.

Objectives: To examine:1. The effect of AT III on mortality in critically ill participants.2. The benefits and harms of AT III.We investigated complications specific and not specific to the trial intervention, bleeding events, the effect on sepsis and disseminated intravascular coagulation (DIC) and the length of stay in the intensive care unit (ICU) and in hospital in general.

Search methods: We searched the following databases from inception to 27 August 2015: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid SP), EMBASE (Ovid SP,), CAB, BIOSIS and CINAHL. We contacted the main authors of trials to ask for any missed, unreported or ongoing trials.

Selection criteria: We included randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status, outcomes published, or language. We contacted the investigators and the trial authors in order to retrieve missing data. In this updated review we include trials only published as abstracts.

Data collection and analysis: Our primary outcome measure was mortality. Two authors each independently abstracted data and resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI). We performed subgroup analyses to assess risk of bias, the effect of AT III in different populations (sepsis, trauma, obstetrics, and paediatrics), and the effect of AT III in patients with or without the use of concomitant heparin. We assessed the adequacy of the available number of participants and performed trial sequential analysis (TSA) to establish the implications for further research.

Main results: We included 30 RCTs with a total of 3933 participants (3882 in the primary outcome analyses).Combining all trials, regardless of bias, showed no statistically significant effect of AT III on mortality with a RR of 0.95 (95% CI 0.88 to 1.03), I² statistic = 0%, fixed-effect model, 29 trials, 3882 participants, moderate quality of evidence). For trials with low risk of bias the RR was 0.96 (95% Cl 0.88 to 1.04, I² statistic = 0%, fixed-effect model, 9 trials, 2915 participants) and for high risk of bias RR 0.94 (95% Cl 0.77 to 1.14, I² statistic = 0%, fixed-effect model, 20 trials, 967 participants).For participants with severe sepsis and DIC the RR for mortality was non-significant, 0.95 (95% Cl 0.88 to 1.03, I² statistic = 0%, fixed-effect model, 12 trials, 2858 participants, moderate quality of evidence).We conducted 14 subgroup and sensitivity analyses with respect to the different domains of risk of bias, but detected no statistically significant benefit in any subgroup analyses.Our secondary objective was to assess the benefits and harms of AT III. For complications specific to the trial intervention the RR was 1.26 (95% Cl 0.83 to 1.92, I² statistic = 0%, random-effect model, 3 trials, 2454 participants, very low quality of evidence). For complications not specific to the trial intervention, the RR was 0.71 (95% Cl 0.08 to 6.11, I² statistic = 28%, random-effects model, 2 trials, 65 participants, very low quality of evidence). For complications other than bleeding, the RR was 0.72 ( 95% Cl 0.42 to 1.25, I² statistic = 0%, fixed-effect model, 3 trials, 187 participants, very low quality of evidence). Eleven trials investigated bleeding events and we found a statistically significant increase, RR 1.58 (95% CI 1.35 to 1.84, I² statistic = 0%, fixed-effect model, 11 trials, 3019 participants, moderate quality of evidence) in the AT III group. The amount of red blood cells administered had a mean difference (MD) of 138.49 (95% Cl -391.35 to 668.34, I² statistic = 84%, random-effect model, 4 trials, 137 participants, very low quality of evidence). The effect of AT III in patients with multiple organ failure (MOF) was a MD of -1.24 (95% Cl -2.18 to -0.29, I² statistic = 48%, random-effects model, 3 trials, 156 participants, very low quality of evidence) and for patients with an Acute Physiology and Chronic Health Evaluation score (APACHE) at II and III the MD was -2.18 (95% Cl -4.36 to -0.00, I² statistic = 0%, fixed-effect model, 3 trials, 102 participants, very low quality of evidence). The incidence of respiratory failure had a RR of 0.93 (95% Cl 0.76 to 1.14, I² statistic = 32%, random-effects model, 6 trials, 2591 participants, moderate quality of evidence). AT III had no statistically significant impact on the duration of mechanical ventilation (MD 2.20 days, 95% Cl -1.21 to 5.60, I² statistic = 0%, fixed-effect model, 3 trials, 190 participants, very low quality of evidence); on the length of stay in the ICU (MD 0.24, 95% Cl -1.34 to 1.83, I² statistic = 0%, fixed-effect model, 7 trials, 376 participants, very low quality of evidence) or on the length of stay in hospital in general (MD 1.10, 95% Cl -7.16 to 9.36), I² statistic = 74%, 4 trials, 202 participants, very low quality of evidence).

Authors' conclusions: There is insufficient evidence to support AT III substitution in any category of critically ill participants including the subset of patients with sepsis and DIC. We did not find a statistically significant effect of AT III on mortality, but AT III increased the risk of bleeding events. Subgroup analyses performed according to duration of intervention, length of follow-up, different patient groups, and use of adjuvant heparin did not show differences in the estimates of intervention effects. The majority of included trials were at high risk of bias (GRADE; very low quality of evidence for most of the analyses). Hence a large RCT of AT III is needed, without adjuvant heparin among critically ill patients such as those with severe sepsis and DIC, with prespecified inclusion criteria and good bias protection.

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Conflict of interest statement

Mikkel Allingstrup declares that there are no conflicts of interest Jørn Wetterslev declares that he is a member of the task force on trial sequential analysis (TSA) at Copenhagen Trial Unit developing and programming TSA (please see www.ctu.dk/tsa) Frederikke B Ravn declares that there are no conflicts of interest Ann Merete Møller declares that there are no conflicts of interest Arash Afshari declares that there are no conflicts of interest

Figures

1
1
Trial sequential analysis of AT III vs placebo or no intervention on number of bleeding events. The Diversity (D‐square) is 0%, the control event proportion is 13.2% and the required information size is estimated for an anticipated relative risk increase of 20% with a type 1 and 2 error risk of 5% and 20% respectively. The cumulative Z‐curve is breaking through the trial sequential monitoring boundary for harm suggesting, even though the required information size has not been reached, that AT III increases the number of bleeding events. The TSA‐adjusted meta‐analysis yields a RR of 1.85 (95% CI 1.35 to 1.85).
2
2
Flow
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.
4
4
Risk of bias graph summarized
5
5
Funnel plot, overall mortality regardless of follow‐up and bias Analysis 1.1
6
6
Trial sequential analysis of all trials with low risk of bias of the effect of AT III on mortality. Cumulative Z‐curve in blue does not cross the trial sequential monitoring boundary (full red line with open diamonds) constructed for a low‐bias heterogeneity‐adjusted information size of 23,634 participants corresponding to a RRR of 5% with an α = 0.05 and a power of 80% (β = 0.20). Only 16.43 % of the required information size has been reached so far.
7
7
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 open diamonds) with a 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 therefore led to rejection of an intervention effect of a RRR of 10% with a power of 80% in 30 randomized trials with a total number of accrued participants of 3882.
8
8
Trial sequential analysis (TSA) of all trials of sepsis and DIC examining the effect of AT III on mortality. Cumulative Z‐curve in blue does not cross the boundary constructed for an information size of 3794 in the meta‐analysis (full red line with open diamonds) with a 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 therefore led to rejection of an intervention effect of a RRR of 10% with a power of 80% in 30 randomized trials with a total number of accrued participants of 2992.
9
9
Trial sequential analysis of all trials of Sepsis and DIC with low risk of bias examining the effect of AT III on mortality. Cumulative Z‐curve in blue does not cross the trial sequential monitoring boundary (full red line with open diamonds) constructed for a low bias heterogeneity adjusted information size of 21,657 participants corresponding to a RRR of 5% with an α = 0.05 and a power of 80% (β = 0.20). Only 13.82 % of the required information size has been reached so far.
1.1
1.1. Analysis
Comparison 1 AT III versus control, Outcome 1 Mortality (subgroup analysis on bias risk).
1.2
1.2. Analysis
Comparison 1 AT III versus control, Outcome 2 Overall mortality (subgroup analysis on median follow‐up).
1.3
1.3. Analysis
Comparison 1 AT III versus control, Outcome 3 Overall mortality (subgroup analysis on duration of intervention).
1.4
1.4. Analysis
Comparison 1 AT III versus control, Outcome 4 Overall mortality (trauma).
1.5
1.5. Analysis
Comparison 1 AT III versus control, Outcome 5 Overall mortality (obstetrics).
1.6
1.6. Analysis
Comparison 1 AT III versus control, Outcome 6 Overall mortality (paediatrics).
1.7
1.7. Analysis
Comparison 1 AT III versus control, Outcome 7 Overall mortality (heparin; Warren 2001 as a trial with adjuvant heparin therapy).
1.8
1.8. Analysis
Comparison 1 AT III versus control, Outcome 8 Overall mortality (heparin; Warren 2001 as a trial without adjuvant heparin therapy).
1.9
1.9. Analysis
Comparison 1 AT III versus control, Outcome 9 Overall mortality (heparin; Warren 2001 data split based on heparin administration).
1.10
1.10. Analysis
Comparison 1 AT III versus control, Outcome 10 Overall mortality among patients with severe sepsis & DIC.
1.11
1.11. Analysis
Comparison 1 AT III versus control, Outcome 11 Complications during the inpatient stay specific to the trial intervention.
1.12
1.12. Analysis
Comparison 1 AT III versus control, Outcome 12 Complications during the inpatient stay not specific to the trial intervention.
1.13
1.13. Analysis
Comparison 1 AT III versus control, Outcome 13 Complication specific to the trial intervention other than bleeding.
1.14
1.14. Analysis
Comparison 1 AT III versus control, Outcome 14 Bleeding events.
1.15
1.15. Analysis
Comparison 1 AT III versus control, Outcome 15 Amount of red blood cells administered.
1.16
1.16. Analysis
Comparison 1 AT III versus control, Outcome 16 Incidence of surgical intervention.
1.17
1.17. Analysis
Comparison 1 AT III versus control, Outcome 17 Severity of sepsis I.
1.18
1.18. Analysis
Comparison 1 AT III versus control, Outcome 18 Severity of sepsis II.
1.19
1.19. Analysis
Comparison 1 AT III versus control, Outcome 19 Incidence of respiratory failure not present at admission.
1.20
1.20. Analysis
Comparison 1 AT III versus control, Outcome 20 Duration of mechanical ventilation.
1.21
1.21. Analysis
Comparison 1 AT III versus control, Outcome 21 Length of stay in hospital.
1.22
1.22. Analysis
Comparison 1 AT III versus control, Outcome 22 Mean length of stay in ICU.
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References

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References to other published versions of this review

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