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Intensive Care Medicine Apr 2016Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties. We assessed the benefits and harms of AT III in critically ill patients. (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Antithrombin III; Antithrombins; Critical Illness; Disseminated Intravascular Coagulation; Humans; Randomized Controlled Trials as Topic; Sepsis
PubMed: 26862016
DOI: 10.1007/s00134-016-4225-7 -
The Cochrane Database of Systematic... Feb 2016Critical illness is associated with uncontrolled inflammation and vascular damage which can result in multiple organ failure and death. Antithrombin III (AT III) is an... (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Anti-Inflammatory Agents; Anticoagulants; Antithrombin III; Critical Illness; Humans; Randomized Controlled Trials as Topic
PubMed: 26858174
DOI: 10.1002/14651858.CD005370.pub3 -
The Cochrane Database of Systematic... May 2015Hepatic veno-occlusive disease (VOD) is a severe complication after haematopoietic stem cell transplantation (HSCT). Different drugs with different mechanisms of action... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hepatic veno-occlusive disease (VOD) is a severe complication after haematopoietic stem cell transplantation (HSCT). Different drugs with different mechanisms of action have been tried in HSCT recipients to prevent hepatic VOD. However, it is uncertain whether high-quality evidence exists to support any prophylactic therapy.
OBJECTIVES
We aimed to determine the effects of various prophylactic therapies on the incidence of hepatic VOD, overall survival, mortality, quality of life (QOL), and the safety of these therapies in people undergoing HSCT.
SEARCH METHODS
We searched the Cochrane Central Registe of Controlled Trials (CENTRAL), MEDLINE, EMBASE, conference proceedings of three international haematology-oncology societies and two trial registries in January 2015, together with reference checking, citation searching and contact with study authors to identify additional studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing prophylactic therapies with placebo or no treatment, or comparing different therapies for hepatic VOD in people undergoing HSCT.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included 14 RCTs. Four trials (612 participants) compared ursodeoxycholic acid with or without additional treatment versus placebo or no treatment or same additional treatment. Two trials (259 participants) compared heparin with no treatment. Two trials (106 participants) compared low molecular weight heparin (LMWH) with placebo or no treatment. One trial (360 participants) compared defibrotide with no treatment. One trial (34 participants) compared glutamine with placebo. Two trials (383 participants) compared fresh frozen plasma (FFP) with or without additional treatment versus no treatment or same additional treatment. One trial (30 participants) compared antithrombin III with heparin versus heparin. One trial compared heparin (47 participants) with LMWH (46 participants) and prostaglandin E1 (PGE1) (47 participants). No trial investigated the effects of danaparoid. The RCTs included participants of both genders with wide age range and disease spectrum undergoing autologous or allogeneic HSCT. Funding was provided by government sources (two studies), research fund (one study), pharmaceutical companies that manufactured defibrotide and ursodeoxycholic acid (two studies), or unclear source (nine studies). All RCTs had high risk of bias because of lack of blinding of participants and study personnel, or other risks of bias (mainly differences in baseline characteristics of comparison groups).Results showed that ursodeoxycholic acid may reduce the incidence of hepatic VOD (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.40 to 0.88; number needed to treat for an additional beneficial outcome (NNTB) 15, 95% CI 7 to 50, low quality of evidence), but there was no evidence of difference in overall survival (hazard ratio (HR) 0.83, 95% CI 0.59 to 1.18, low quality of evidence). It may reduce all-cause mortality (RR 0.70, 95% CI 0.50 to 0.99; NNTB 17, 95% CI 8 to 431, low quality of evidence) and mortality due to hepatic VOD (RR 0.27, 95% CI 0.09 to 0.87; NNTB 34, 95% CI 16 to 220, very low quality of evidence). There was no evidence of difference in the incidence of hepatic VOD between treatment and control groups for heparin (RR 0.47, 95% CI 0.18 to 1.26, very low quality of evidence), LMWH (RR 0.27, 95% CI 0.06 to 1.18, very low quality of evidence), defibrotide (RR 0.62, 95% CI 0.38 to 1.02, low quality of evidence), glutamine (no hepatic VOD in either group, very low quality of evidence), FFP (RR 0.66, 95% CI 0.20 to 2.17, very low quality of evidence), antithrombin III (RR 0.13, 95% CI 0.01 to 2.15, very low quality of evidence), between heparin and LMWH (RR 1.96, 95% CI 0.80 to 4.77, very low quality of evidence), between heparin and PGE1 (RR 1.20, 95% CI 0.58 to 2.50, very low quality of evidence), and between LMWH and PGE1 (RR 0.61, 95% CI 0.24 to 1.55, very low quality of evidence). There was no evidence of difference in survival between treatment and control groups for heparin (92.6% vs. 88.7%) and defibrotide (HR 1.04, 95% CI 0.54 to 2.02, low quality of evidence). There were no data on survival for trials of LMWH, glutamine, FFP, antithrombin III, between heparin and LMWH, between heparin and PGE1, and between LMWH and PGE1. There were no data on quality of life (QoL) for any trials. Eleven trials reported adverse events. There was no evidence of difference in the frequency of adverse events between treatment and control groups except for one trial showing that defibrotide resulted in more adverse events compared with no treatment (RR 18.79, 95% CI 1.10 to 320.45). These adverse events included coagulopathy, gastrointestinal disorders, haemorrhage and microangiopathy. The quality of evidence was low or very low due to bias of study design, and inconsistent and imprecise results.
AUTHORS' CONCLUSIONS
There is low or very low quality evidence that ursodeoxycholic acid may reduce the incidence of hepatic VOD, all-cause mortality and mortality due to VOD in HSCT recipients. However, the optimal regimen is not well-defined. There is insufficient evidence to support the use of heparin, LMWH, defibrotide, glutamine, FFP, antithrombin III, and PGE1. Further high-quality RCTs are needed.
Topics: Antithrombin III; Cause of Death; Cholagogues and Choleretics; Female; Glutamine; Hematopoietic Stem Cell Transplantation; Heparin, Low-Molecular-Weight; Hepatic Veno-Occlusive Disease; Humans; Male; Plasma; Polydeoxyribonucleotides; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid
PubMed: 26017019
DOI: 10.1002/14651858.CD009311.pub2 -
Journal of Vascular Surgery Feb 2014The purpose of this study was to summarize the current evidence of the association between markers of hemostasis and both the presence and size of abdominal aortic... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The purpose of this study was to summarize the current evidence of the association between markers of hemostasis and both the presence and size of abdominal aortic aneurysms (AAAs).
METHODS
A systematic review and meta-analysis was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines by use of the search terms "aneurysm AND abdominal AND aortic AND coagulation" NOT "thoracic." Outcome data including concentration of hemostatic marker, number of patients, and significance level were recorded.
RESULTS
A total of 22 nonrandomized studies were included in the analysis, with a total of 9862 patients. Fibrinogen mean difference (MD) (0.43 g/L; 95% confidence interval [CI], 0.28-0.58 g/L; P ≤ .00001), D-dimer MD (325.82 ng/mL; 95% CI, 199.74-451.89 ng/mL; P ≤ .00001), and thrombin-antithrombin III complex MD (5.58 g/L; 95% CI, 3.34-7.83 g/L; P ≤ .0001) were significantly elevated in the presence of AAAs. Tissue plasminogen activator, prothrombin fragments F1+F2, and platelet count were not shown to be significantly different between patients with and those without AAAs. Meta-regression of studies reporting plasma D-dimer concentration and aneurysm diameter suggests a strong and significant association (r(2) = 0.94; P ≤ .0001).
CONCLUSIONS
This study suggests that the presence of AAAs is associated with increased fibrin turnover, fibrinolysis, and thrombin generation, as shown by increased levels of fibrinogen, D-dimer, and thrombin-antithrombin III complex. This is clinically relevant because markers of hemostasis are independent risk factors for cardiovascular events, highlighting the necessity of addressing all modifiable cardiovascular risk factors in patients with AAAs. Furthermore, the finding that plasma D-dimer concentration appears to have a linear relationship with aneurysm diameter may be useful as a future biomarker of AAAs.
Topics: Antithrombin III; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Biomarkers; Dilatation, Pathologic; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hemostasis; Humans; Peptide Hydrolases; Prognosis; Risk Factors
PubMed: 24461868
DOI: 10.1016/j.jvs.2013.10.088 -
BMJ (Clinical Research Ed.) Dec 2007To evaluate the benefits and harms of antithrombin III in critically ill patients. (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Anticoagulants; Antithrombin III; Critical Care; Critical Illness; Humans; Length of Stay; Quality of Life; Randomized Controlled Trials as Topic; Respiration, Artificial; Risk Factors
PubMed: 18037615
DOI: 10.1136/bmj.39398.682500.25 -
The Cochrane Database of Systematic... Oct 2006Acquired Antithrombin (AT) deficiency is a common and prognostically important finding in sick preterm infants with respiratory distress syndrome (RDS). It has been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acquired Antithrombin (AT) deficiency is a common and prognostically important finding in sick preterm infants with respiratory distress syndrome (RDS). It has been hypothesised that AT concentrate may improve clinical outcomes in preterm infants with RDS.
OBJECTIVES
To determine whether the administration of AT concentrate decreases mortality in preterm infants with RDS compared with placebo or no treatment.
SEARCH STRATEGY
An electronic literature search in the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE in August 2006 was performed. No language restriction was applied. References from identified studies were cross-checked for possible additional studies. Experts in the field and pharmaceutical companies were contacted for unpublished data. Abstracts of the American Society of Pediatric Research and European Society of Pediatric Research meetings (1983-2005) were searched and authors of relevant studies were contacted to obtain additional information.
SELECTION CRITERIA
Randomized controlled trials comparing any dose and duration of AT therapy with placebo or no treatment in preterm infants with RDS.
DATA COLLECTION AND ANALYSIS
Two reviewers independently extracted data from included studies regarding mortality, intraventricular hemorrhage, mechanical ventilation, and other reported events in the clinical course of the patients. Data for similar outcomes were combined where appropriate, using a fixed-effects model in MetaView 4.2 (Update Software).
MAIN RESULTS
Two trials consisting of 182 preterm infants, fulfilled the inclusion criteria. Mean gestational age of patients included was 28 weeks. In one trial, patients had to be intubated and ventilated for RDS to be eligible for the study. In the other trial, RDS was not mentioned as an inclusion criteria, however the vast majority of infants in the study received surfactant. No individual trial showed a significant difference in mortality. One of the trials was stopped early because of an increase in deaths in the AT group. The pooled analysis for mortality within the first week of life showed a typical relative risk of 2.67 (95% CI 0.72-9.83) in favour of the control group. Only the trial that was stopped early followed the infants long enough to report neonatal mortality. This trial reported 7 deaths (11.5%) in the AT group and two deaths (3.3%) in the placebo group within 28 days of life. Secondary outcomes included days of mechanical ventilation and supplemental oxygen which were only reported in 1 trial. Both outcomes were in favour of the control group and statistically significant (p < 0.05).
AUTHORS' CONCLUSIONS
Preterm infants with RDS are unlikely to benefit from AT treatment and may be harmed.
Topics: Anticoagulants; Antithrombin III; Antithrombins; Humans; Infant, Newborn; Infant, Premature; Pulmonary Surfactants; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome, Newborn
PubMed: 17054254
DOI: 10.1002/14651858.CD005383.pub2