Strategy for Cardiovascular Surgery in Patients with Antithrombin III Deficiency.

Antithrombin III (ATIII) deficiency is a rare disorder in which thrombosis can be induced by stimuli that do not usually lead to thrombus formation, including minor injuries and surgery. Therefore, patients with ATIII deficiency undergoing cardiovascular surgery that involves heparinization require careful perioperative management. We experienced five patients with ATIII deficiency who underwent cardiovascular surgery and were managed with ATIII replacement. By administration of ATIII concentrate, preoperative ATIII activity was maintained at ≥120% and postoperative ATIII activity at ≥80%. All five patients were treated successfully without postoperative complications such as hemorrhage or thrombosis. In patients with ATIII deficiency undergoing cardiac surgery, it is important to perform ATIII replacement to achieve preoperative ATIII activity ≥120% and postoperative ATIII activity ≥80%, while the activated clotting time (ACT) is maintained at >400 seconds during cardiopulmonary bypass. In addition, long-term postoperative anticoagulant therapy is necessary in hereditary ATIII deficiency patients with a history of thrombosis.

The efficacy and associated bleeding complications of recombinant antithrombin supplementation among intensive care unit patients.

INTRODUCTION: The aim of this study was to evaluate the efficacy and complications of recombinant antithrombin (rAT) supplementation for adult patients with disseminated intravascular coagulation (DIC) compared with conventional plasma derived AT (pAT) treatment in the intensive care unit. MATERIALS AND METHODS: This study was performed in a single national university hospital in Japan. Adult patients from April 2015 to March 2016 with DIC were divided into two groups based on the type of AT agent used: the pAT group (n=24) and the rAT group (n=21). Patient demographics, medical history, diagnosis, blood tests, various clinical scores, AT activity, complications, and clinical outcome were collected and analyzed retrospectively. RESULTS: Significantly higher SIRS and APACHEII scores were confirmed in the rAT group than the pAT group. The initial dose of AT was significantly higher in the rAT group than in the pAT group. ATIII values before and after initial supplementation and during their ten-day clinical course were statistically similar between two groups. During the same period, 10 bleeding adverse events were found and there was no significant difference between both groups. Significantly more cases of the rAT group were administered with recombinant thrombomodulin concomitantly than those of the pAT group. Despite significantly more severe patients in rAT group, the clinical outcomes were the same in each group. CONCLUSIONS: Compared with pAT, the supplementation of rAT indicates clinical effectiveness without increasing the risk of bleeding complications in adult DIC patients with low AT activity.

Antithrombin III for critically ill patients.

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.

A Pilot Study of Antithrombin Replacement Prior to Cardiopulmonary Bypass in Neonates.

Neonates have low levels of antithrombin. Inadequate anticoagulation during cardiopulmonary bypass (CPB) due to low antithrombin activity may result in a poor preservation of the coagulation system during bypass. We hypothesize that antithrombin replacement to neonates prior to CPB will preserve the hemostatic system and result in less postoperative bleeding. A randomized, double-blinded, placebo-controlled pilot study of antithrombin replacement to neonates prior to CPB was conducted. Preoperative antithrombin levels determined the dose of recombinant antithrombin or placebo to be given. Antithrombin levels were measured following the dosing of the antithrombin/placebo, after initiation of bypass, near the completion of bypass, and upon intensive care unit admission. Eight subjects were enrolled. No subject had safety concerns. Mediastinal exploration occurred in two antithrombin subjects and one placebo subject. Antithrombin activity levels were significantly higher in the treated group following drug administration; levels continued to be higher than preoperatively but not different from the placebo group at all other time points. Total heparin administration was less in the antithrombin group; measurements of blood loss were similar in both groups. A single dose of recombinant antithrombin did not maintain 100% activity levels throughout the entire operation. Although no safety concerns were identified in this pilot study, a larger trial is necessary to determine clinical efficacy.

Management of Heparin-Resistant Patients with Benefits? Maximizing Biocompatibility in Cardiopulmonary Bypass: Combining ATryn® Recombinant Antithrombin III and Carmeda® Heparin-Bonded Perfusion Circuits: A Case Series.

As many as 25% of our cardiopulmonary bypass (CPB) patients have a diminished heparin response and fail to reach a therapeutic activated clotting time (ACT). We treat a majority of these patients with antithrombin III (ATryn®, recombinant antithrombin III [rhAT], rEVO Biologics). Our current CPB circuit uses Medtronic Carmeda® coating. We observed less post-operative bleeding in a number of patients treated with rhAT. We theorized that adding rhAT would allow patients with diminished heparin response to safely achieve a therapeutic ACT. On the basis of our postoperative bleeding observations, we wondered if using rhAT with a heparin-bonded CPB circuit enhanced its biocompatibility and perhaps improved patient outcomes. Data were collected on 15 patients undergoing CPB who received antithrombin III (AT) replacement therapy for diminished heparin response. We used patient data from 2012, prior to rhAT usage for comparison. All patients achieved therapeutic ACT after rhAT administration. We also observed decreased postoperative atrial fibrillation rates, improved platelet preservation, decreased intensive care unit and ventilator times in patients receiving rhAT compared to rates commonly observed at our center. Heparin-resistant patients can be treated with rhAT to achieve therapeutic ACTs. Our observations suggest that the use of rhAT in conjunction with Carmeda® heparin-bonded circuits may also have a positive benefit on some of the well-established negative clinical consequences of CPB and improve patient outcomes.

Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency.

Antithrombin (AT) deficiency is a rare hereditary thrombophilia with a mean prevalence of 0.02 % in the general population, associated with a more than ten-fold increased risk of venous thromboembolism (VTE). Within this multicenter retrospective clinical analysis, female patients with inherited AT deficiency were evaluated concerning the type of inheritance and extent of AT deficiency, medical treatment during pregnancy and postpartally, VTE risk as well as maternal and neonatal outcome. Statistical analysis was performed with SPPS for Windows (19.0). A total of 18 pregnancies in 7 patients were evaluated, including 11 healthy newborns ≥37th gestational weeks (gw), one small for gestational age premature infant (25th gw), two late-pregnancy losses (21st and 28th gw) and four early miscarriages. Despite low molecular weight heparin (LMWH) administration, three VTE occurred during pregnancy and one postpartally. Several adverse pregnancy outcomes occurred including fetal and neonatal death, as well as severe maternal neurologic disorders occurred. Patients with substitution of AT during pregnancy in addition to LMWH showed the best maternal and neonatal outcome. Close monitoring with appropriate anticoagulant treatment including surveillance of AT levels might help to optimize maternal and fetal outcome in patients with hereditary AT deficiency.

[Therapy with high-doses of antithrombin III in patients with septic shock and agranulocytosis].

OBJECTIVE: The aim of the study was to assess efficacy of high-doses ofantithrombin 111 (AT) for treatment of septic shock in patients with an agranulocytosis. DESIGN: Prospective, controlled study. PATIENTS: 29 patients from 18 to 74 years old, with blood diseases complicated with septic shock Dates of study: from 2006 to 2012. METHODS: The patients were randomized into two groups. Group-1 included 14 patients, who did not receive AT and group-2 included 15 patients who received AT. RESULTS: Demographic indicators, condition severity according to APACHE II, level of thrombocytopenia, levels ofplasma procalcitonin, interleukin-6 (IL-6) and C-reactive protein (CRP) were the same in both groups. Level of AT was decreased in both groups; however it was higher in the group-1 (50% vs. 60%, p < 0.05). In the group-1, microorganisms were found in the blood of 9 patients. In the group-2, the microorganisms were found in the blood of 11 patients. Inflammation markers were decreased after the treatment of septic shock in both groups (p<0.05). The decreasing of procalcitonin in group-1 was from 43.8 to 1 ng/ml in 14 days and from 12.8 to 1.6 ng/ml in 7 days in group-2. The decreasing of CRP in group-1 was from 224 to 114 mg/l in 7 days and from 146 to 60 mg/l in 14 days in group-2. The decreasing of IL-6 in group-1 was from 1617 to 100 pg/ml in 3 days and from 5895 to 77 pg/ml in 7 days in group-2. A level of AT was increased only in group-2 (under 12% per day). 28-day survival was higher in group-2 (60 +/- 13% vs. 45 +/- 13%, p<0.05). We did not find any complications of the treatment with AT concentrate. CONCLUSION: Treatment of septic shock with high-doses of antithrombin III was effective and safe in patients with an agranulocytosis.

Retrospective evaluation of antithrombin III supplementation in neonates and infants receiving enoxaparin for treatment of thrombosis.

BACKGROUND: Thromboembolic events are occurring at increasing rates in neonates and infants. At Children's Mercy Hospitals and Clinics, antithrombin III (AT3) concentrates are often used in combination with enoxaparin to supplement physiologically low AT3 levels. Theoretically, AT3 enhances the anticoagulant activity of enoxaparin and results in decreased time to therapeutic anti-Xa levels. No data exist on use of AT3 for this indication. PROCEDURE: This retrospective study compared time to therapeutic anti-Xa levels in patients <1 year of age receiving enoxaparin with AT3 (Group 1) and without AT3 (Group 2) for treatment of thrombosis. Primary objective was to compare time to therapeutic anti-Xa levels (0.5-1 U/ml) between groups. Secondary objectives included comparison of the initial and therapeutic dose of enoxaparin, enoxaparin dose changes, AT3 supplementation, and level monitoring. Bleeding events and cost were also evaluated. Statistical tests included Schuirmann's two one-sided tests for equivalence and general linear models/logistic regression for independent effects of age, critical illness, and timing of AT3. RESULTS: Mean time to therapeutic anti-Xa levels were not equivalent between Groups 1 and 2 (80.7 vs. 65.2 hours; P = 0.28). Initial enoxaparin dose and number of dose changes were equivalent. Group 1 required higher doses of enoxaparin to achieve therapeutic anti-Xa levels. Age, critical illness, and timing of AT3 had no effect on time to therapeutic anti-Xa levels. Bleeding events were not equivalent between Groups 1 and 2 (14.3% vs. 3.9%; P = 0.55). CONCLUSION: Supplementation with AT3 did not decrease time to therapeutic anti-Xa levels, added significant cost, and was associated with increased bleeding events.

Bioequivalence of two intravenous formulations of antithrombin III: a two-way crossover study in healthy Korean subjects.

BACKGROUND: Treatment with antithrombin (AT)-III is indicated for patients with sepsis or hereditary AT deficiency. OBJECTIVE: The purpose of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of 2 AT-III formulations in healthy Korean volunteers to satisfy the regulatory requirements for bioequivalence for marketing purposes. METHODS: A single-center, single-dose, open-label, randomized, 2-period, 2-sequence crossover study was conducted in healthy Korean volunteers. Blood samples for the drug analysis were collected for up to 216 hours after drug administration. Participants received either the test or reference formulation of AT-III 100 U/kg IV for 20 minutes in the first period and the alternative formulation in the second period. Both the AT-III activity and antigen (Ag) were measured for the analysis of pharmacokinetic properties, and the prothrombin time and the activated partial thromboplastin time were assessed for the analysis of pharmacodynamic properties. Because AT-III is an endogenous compound, the analysis used data corrected from baseline values. The tolerability of the 2 formulations was also assessed based on physical examinations including vital sign measurements, laboratory tests, and 12-lead ECG. RESULTS: Of the 20 subjects enrolled (mean [SD] age, height, and weight, 25.3 [2.3] years, 175.3 [4.5] cm, and 67.4 [6.3] kg, respectively), 19 completed both treatment periods; 1 subject withdrew consent for personal reasons. The observed mean (SD) Cmax, AUClast, and AUC0-∞ of AT-III activity were, respectively, 279.24% (35.92), 14,364.10 (2325.25) %·h, and 17,526.38 (3150.81) %·h with the test formulation and 249.75% (31.96), 12,962.95 (1897.52) %·h, and 15,957.67 (3189.21) %·h with the reference formulation. The observed mean (SD) Cmax, AUClast, and AUC0-∞ of AT-III Ag were 62.58 (5.66) mg/dL, 3051.94 (401.87) mg/dL·h, and 3639.80 (726.01) mg/dL·h, respectively, with the test formulation and 58.63 (5.27) mg/dL, 2805.08 (272.38) mg/dL·h, and 3340.00 (428.46) mg/dL·h with the reference formulation. The geometric mean ratios (90% CI) of the log-transformed data for AT-III activity between the 2 formulations were 1.11494 (1.08994-1.14053) for Cmax, 1.11305 (1.05435-1.17503) for AUClast, and 1.11527 (1.03754-1.19889) for AUC0-∞; corresponding values for AT-III Ag were 1.08802 (1.06258-1.11405), 1.10905 (1.05804-1.16242), and 1.11460 (1.02058-1.21726). During the study period, 8 adverse events were reported, and all were transient, mild, and resolved completely during the treatment period. CONCLUSION: The results of the present study showed that these 2 AT-III formulations met the regulatory criteria for pharmacokinetic bioequivalence with respect to AT-III activity and Ag in these healthy Korean subjects. ClinicalTrials.gov identifier: NCT00846274.

Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency. An update.

Antithrombin (AT) functions as a potent natural anticoagulant and serine protease inhibitor that inactivates many enzymes in the coagulation cascade. Antithrombin also possesses antiinflammatory properties, many of which are mediated by its actions as an anticoagulant. Hereditary AT deficiency is a rare, underrecognised medical condition that is associated with inadequate endogenous anticoagulation thought to result from impaired inhibition of serine protease coagulation factors. Inherited as an autosomal dominant trait, congenital AT deficiency typically reduces functional AT levels to 40-60% of normal. As a result, individuals with hereditary AT deficiency have a > or = 50% lifetime risk of venous thromboembolism (VTE). Specifically, AT deficiency is associated with a three- to seven-fold higher risk of VTE compared with other thrombophilias. Thus, maintaining adequate levels of AT during high-risk periods is an important treatment goal. Long-term anticoagulant thromboprophylaxis is not recommended in asymptomatic patients with AT deficiency because of the increased risk of haemorrhage. However, treatment guidelines recommend short-term thromboprophylaxis in high-risk clinical settings, including surgery, trauma, and management of pregnancy, labour, and delivery. The goal of treatment for patients with hereditary AT deficiency is an initial increase in AT activity to > or = 120% of normal levels followed by maintenance of AT activity at > or = 80% of normal levels. Plasma-derived AT, heparin, fresh frozen plasma, and human recombinant AT are treatment options for individuals with hereditary AT deficiency. The objective of this review is to discuss hereditary AT deficiency and the role of AT replacement therapy in the treatment of patients with this congenital disorder.

Antithrombin Cambridge II (A384S) supports a role for antithrombin deficiency in arterial thrombosis.

Although the control of thrombin in the microvasculature at the endothelial cell surface is crucial to prevent atherothrombosis, the role of antithrombin in arterial thrombosis is unclear. It is widely considered that antithrombin deficiency is unlikely to contribute to arterial thrombosis, but no convincing epidemiological study has been performed because of the low frequency of this deficiency. In this study we evaluated the role in myocardial infarction (MI) of a relatively common mutation affecting antithrombin gene (A384S: Antithrombin Cambridge II) that has functional features that may impair the right control of thrombogenic events caused by injury to the vascular wall. Moreover, this deficiency, which is not detected using common methods to diagnose antithrombin deficiency, also increases the risk of venous thrombosis. We included 1,224 patients with MI (691 consecutive patients and 533 survivors of a premature event), and 1,649 controls. The mutation was identified in 0.3% of controls, but 0.8% of MI patients. After adjusting for sex and other cardiovascular risk factors, the antithrombin Cambridge II significantly increased 5.66-fold the risk of MI (95% CI: 1.53-20.88; p = 0.009). Interestingly, young patients had the highest risk of MI associated with the mutation (OR: 9.98; 95%CI: 1.60-62.24; p = 0.009). This is the first epidemiological study that supports a role for antithrombin deficiency in arterial thrombosis. These results suggest that deficiency of antithrombin may be an independent risk factor for MI that has been underestimated, but larger studies are needed to confirm the relevance of inhibitors of thrombin in arterial thrombosis.

Effects of antithrombin III in patients with disseminated intravascular coagulation diagnosed by newly developed diagnostic criteria for critical illness.

A study was conducted to test the hypotheses that antithrombin III (antithrombin) improves disseminated intravascular coagulation (DIC) when applied to DIC patients diagnosed by sensitive criteria and that the administration of high-dose antithrombin is a beneficial treatment for DIC. Twenty-three DIC patients diagnosed based on the Japanese Association for Acute Medicine (JAAM) DIC diagnostic criteria were treated with either high-dose (60 IU/kg/day) or low-dose (30 IU/kg/day) antithrombin concentrates for 3 days. The clinical conditions that cause DIC were restricted to systemic inflammatory response syndrome (SIRS) and sepsis. Data of antithrombin activity, platelet counts, coagulation and fibrinolytic markers, and DIC scores before antithrombin administration (day 0), on days 1 to 3, and on day 7 were retrospectively collected from computer-based records. Patients who met the JAAM DIC criteria were administered either high-dose (12 patients) or low-dose (11 patients) antithrombin. The patients' backgrounds and antithrombin activity (high dose, 51.5 +/- 14.5%; low dose, 62.6 +/- 19.3%; P = .153) on day 0 were identical in the 2 groups. The JAAM DIC score and prothrombin time ratio on day 7 significantly improved when compared with those on day 0. However, mortality at 28 days as well as interaction within the antithrombin doses administered showed no difference. There were also no differences in the time course of the platelet counts, coagulation and fibrinolytic markers, and DIC scores in the 2 groups. The authors conclude that the effects of antithrombin on prognosis and coagulation and fibrinolytic parameters are independent of the doses administered in patients with SIRS/sepsis-associated DIC.

Antithrombin III for critically ill patients.

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. OBJECTIVES: To assess the benefits and harms of AT III in critically ill patients. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to November 2006). We contacted authors and manufacturers in the field. SELECTION CRITERIA: We included all randomized clinical trials, irrespective of blinding or language, that compared AT III with no intervention or placebo in critically ill patients. DATA COLLECTION AND ANALYSIS: Our primary outcome measure was mortality. We each independently abstracted data and resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as relative risks (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, obstetric, and paediatric patients), 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 a trial sequential analysis to establish the implications for further research. MAIN RESULTS: We included 20 randomized trials with a total of 3458 participants; 13 of these trials had high risk of bias. When we combined all trials, AT III did not statistically significantly reduce overall mortality compared with the control group (RR 0.96, 95% CI 0.89 to 1.03; no heterogeneity between trials). A total of 32 subgroup and sensitivity analyses were carried out. Analyses based on risk of bias, different populations, and the role of adjuvant heparin gave insignificant differences. AT III reduced the multiorgan failure score among survivors in an analysis involving very few patients. AT III increased bleeding events (RR 1.52, 95% CI 1.30 to 1.78). AUTHORS' CONCLUSIONS: AT III cannot be recommended for critically ill patients based on the available evidence. A randomized controlled trial of AT III, without adjuvant heparin, with prespecified inclusion criteria and good bias protection is needed.

Activity-guided antithrombin III therapy in severe surgical sepsis: efficacy and safety according to a retrospective data analysis.

Recent controlled studies that evaluated the efficacy of an adjuvant antithrombin (AT) III therapy in severe sepsis used a uniform AT-III dose and duration of therapy and did not adjust to the actual AT-III deficit. It was the aim of the present study to explore if surgical patients with severe sepsis might have a treatment benefit from an activity-guided AT-III therapy. We performed a retrospective cohort analysis using an intensive care unit (ICU) database. To examine the effect of AT-III on outcome and on red cell transfusion rate, multivariate generalized additive models (GAMs), Cox-type additive hazard regression models, and propensity score adjustments were used. Five hundred forty-five postoperative surgical patients requiring ICU therapy because of severe sepsis were analyzed. Antithrombin III was given to those patients believed to be at a high risk of dying. Antithrombin III therapy was guided by the individual AT-III activity and aimed at the maintenance of an activity of at least 100%. Antithrombin III supplementation was discontinued after the plasma AT-III activity had been persistently normal without simultaneous AT-III infusion. We found that patients receiving additional AT-III (n = 230) were sicker than those on standard therapy (n = 315; admission Acute physiology and chronic health evaluation II score, 19.8 +/- 7.3 vs. 17.9 +/- 7.1 [mean +/- SD]; P < 0.005). Correspondingly, 28-day mortality was higher in patients who had an additional AT-III therapy than in those on standard therapy (46.3% vs. 36.9%; P < 0.03), as was the number of red cell units transfused during ICU stay (21.5 +/- 26.7 vs. 9.3 +/- 12.1; P < 0.001). At multivariate analysis, there was no significant effect of AT-III therapy on 28-day mortality (GAM: odds ratio, 1.012; 95% confidence interval [CI], 0.651 - 1.573; P = 0.957) and 90-day survival time (Cox-type additive hazard regression: hazard ratio, 1.034; 95% CI, 0.779 - 1.387; P = 0.794). However, AT-III therapy was associated with a significantly higher frequency of red cell unit transfusion (GAM/zero-inflated Poisson: estimate, 1.26; 95% CI, 1.15 - 139; P < 0.001). Our results suggest that there seems to be no relevant effect of an activity-guided AT-III therapy on the prognosis of surgical patients with severe sepsis. However, transfusion frequency rises by AT-III therapy.

Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial.

BACKGROUND: The optimal anticoagulant regimen for percutaneous coronary intervention (PCI) remains to be determined. Otamixaban, a selective and direct inhibitor of factor Xa, was investigated in patients undergoing nonurgent percutaneous coronary intervention. METHODS AND RESULTS: In this double-blind, double-dummy, parallel-group, dose-ranging trial, 947 patients were randomly assigned to either 1 of 5 weight-adjusted otamixaban regimens or weight-adjusted unfractionated heparin (UFH) before percutaneous coronary intervention. The primary end points were change in prothrombin fragments 1+2 (F1+2), and anti-factor Xa activity. The main secondary end points were Thrombolysis In Myocardial Infarction (TIMI) bleeding at day 3 or hospital discharge (whichever came first) and 30-day ischemic events. The median change in F1+2 from baseline to the end of infusion was greater with the highest otamixaban dose compared with UFH (-0.3 versus -0.2 ng/mL, P=0.008). Anti-factor Xa levels were 65, 155, 393, 571, and 691 ng/mL with otamixaban doses 1 to 5, respectively. Significant TIMI bleeding (major or minor) occurred in 2.0%, 1.9%, 3.8%, 3.9%, and 2.6% of patients receiving otamixaban doses 1 to 5, respectively, and in 3.8% of patients receiving UFH. Four TIMI major bleeds were observed. Ischemic events occurred in 5.8%, 7.1%, 3.8%, 2.5%, and 5.1% of patients receiving otamixaban doses 1 to 5, respectively, and in 5.6% of patients receiving UFH. CONCLUSIONS: Otamixaban reduced F1+2 significantly more than UFH at the highest dose regimen, whereas no significant difference in the incidence of TIMI bleeding was observed between the otamixaban and UFH groups. These results set the stage for adequately powered clinical outcome trials of selective direct factor Xa inhibition in patients with acute coronary syndromes.

Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects.

Anticoagulants are often dose adjusted, or their use restricted, in patients with extremes of body weight. Rivaroxaban (BAY 59-7939) is a novel, oral, direct factor Xa inhibitor in clinical development. This was a randomized, single-blind, placebo-controlled, parallel-group study in healthy male and female subjects to assess the effect of extreme body weight (< or = 50 kg and >120 kg), and gender, on the safety, tolerability, pharmacokinetics, and pharmacodynamics of rivaroxaban 10 mg, compared with subjects of normal weight (70-80 kg). Rivaroxaban was well tolerated. Cmax of rivaroxaban was unaffected in subjects >120 kg but was increased by 24% in subjects weighing < or = 50 kg, resulting in a small (15%) increase in prolongation of prothrombin time, which was not considered clinically relevant. The area under the curve was unaffected by body weight or gender. No other clinically relevant differences were observed, suggesting that rivaroxaban is unlikely to require dose adjustment for body weight or gender.

Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin.

A randomised, prospective, placebo-controlled phase III multicentre clinical trial (KyberSept) has been performed to test the efficacy of high-dose antithrombin therapy in patients with severe sepsis. Concomitant low-dose heparin has been routinely given in two thirds of patients for deep vein thrombosis prophylaxis. This study analyses heparin - antithrombin interactions in terms of long-term mortality, adverse events, and thromboembolic events. From a total of 2,314 patients with severe sepsis (placebo: n = 1,157; antithrombin: n = 1,157) 1,616 patients (placebo: 811, antithrombin: 805) received heparin concomitantly with study drug (antithrombin 30,000 IU) over four days, whereas 698 patients (346 and 352, respectively) did not. In patients with no concomitant heparin, 28-day mortality was lower with antithrombin than with placebo (37.8% vs. 43.6%; absolute reduction: 5.8%; risk ratio: 0.860 [0.725-1.019]), which increased until day-90 (44.9% vs. 52.5%; absolute reduction: 7.6%; risk ratio: 0.851 [0.735-0.987]). In patients with concomitant heparin, no effect of antithrombin on mortality was seen (28-day mortality: 39.4% vs. 36.6%; absolute increase: 2.8%; risk ratio: 1.08 [0.96-1.22]). Frequency of use of concomitant heparin increased during conduct of the study. Increased bleeding incidences were reported with antithrombin plus concomitant heparin as compared to antithrombin alone. Rates of thromboembolic events were similar when antithrombin was given with or without concomitant heparin. In the treatment of severe sepsis, high-dose antithrombin may sufficiently protect against development of venous thromboembolism when no concomitant heparin is given. Combined administration of the two increases bleeding risk and probably abolishes efficacy of antithrombin.

High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety.

OBJECTIVE: To explore if patients with severe sepsis and with a predicted high risk of death (according to the Simplified Acute Physiology Score II) might have a treatment benefit from high-dose antithrombin III. DESIGN: Subgroup analysis of a randomized, placebo-controlled, double-blind, prospective phase III study. SETTING: Unifactorial and multifactorial reanalysis of prospectively defined populations from the KyberSept trial. PATIENTS: We studied 1,008 patients (43.6% of the overall intention-to-treat population, n = 2,314) with a predicted mortality rate of 30-60% at study entry as defined by the Simplified Acute Physiology Score II. INTERVENTIONS: Patients were randomized in a 1:1 fashion to receive either high-dose antithrombin III (30,000 IU intravenously over the period of 4 days) or placebo. MEASUREMENTS AND MAIN RESULTS: In a Kaplan-Meier analysis of patients with a predicted mortality of 30-60%, the survival time when followed up for 90 days after admission was increased in the high-dose antithrombin III group compared with placebo (p = .04). If heparin was avoided during the 4-day treatment phase with high-dose antithrombin III (n = 140) or placebo (n = 162), the treatment effect appeared to be even more pronounced: 28-day mortality rate, 35.7% vs. 44.4% (risk ratio, 0.804; 95% confidence interval, 0.607-1.064); 56-day mortality rate, 39.9% vs. 52.2% (risk ratio, 0.764; 95% confidence interval, 0.593-0.984); 90-day mortality rate, 42.8% vs. 55.1% (risk ratio, 0.776; 95% confidence interval, 0.614-0.986). Like in the overall population, the percentage with any bleeding was increased in patients receiving high-dose antithrombin III compared with placebo. Survival rates were in favor of high-dose antithrombin III in patients both with and without bleeding complications. CONCLUSIONS: Treatment with high-dose antithrombin III may increase survival time up to 90 days in patients with severe sepsis and high risk of death. This benefit may even be stronger when concomitant heparin is avoided.

Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality. OBJECTIVES: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC. PATIENTS AND METHODS: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination. RESULTS: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02). CONCLUSIONS: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment.