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CRITICAL CARE AND TRAUMA

Early Administration of High-Dose Antithrombin in Severe Sepsis: Single Center Results from the KyberSept-Trial

Alain Eid, MD^*, Christian J. Wiedermann, MD, and Gary T. Kinasewitz, MD

From the *Division of Pulmonary and Critical Care, CO Springs Memorial Hospital, CO Springs, Colorado; Division of Internal Medicine, Department of Medicine, Central Hospital of Bolzano, Bolzano, Italy; and Pulmonary and Critical Care Medicine, University of Oklahoma Health Science Center, Oklahoma.

Address correspondence and reprint requests to Dr. Christian J. Wiedermann, Department of Internal Medicine, Central Hospital of Bolzano, Lorenz Büohler St. 5, 39100 Bolzano (BZ), Italy. Address e-mail to Echristian.wiedermann{at}asbz.it.

	Abstract

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BACKGROUND: The overall finding in the KyberSept trial of no treatment effect of high-dose antithrombin (AT) in severe sepsis was inconsistent for the primary outcome, 28-day mortality, possibly because of patient heterogeneity. No data have been reported on the effects of AT therapy administered early in severe sepsis when microcirculation is disturbed but irreversible organ damage has not yet developed.

OBJECTIVE: We report the post hoc results of the KyberSept trial in patients with severe sepsis treated at a single center early after new onset organ failure.

METHODS: All study participants from a United States tertiary care intensive care unit were analyzed. Patients had been randomized 1:1 (placebo: n = 41; AT: n = 40) to receive AT (30,000 IU IV over a period of four days) or placebo within 48 h.

RESULTS: Baseline variables were well balanced between groups. Eighty percent of patients (n = 65) received study drug within 24 h after onset of severe sepsis; 94% (n = 76) received study drug within 48 h. Nine of 40 participants in the AT group (22.5%) had new organ dysfunction during the first 7 days which was not present at baseline compared with 17 of 39 subjects (43.6%) in the placebo group (P = 0.058; two participants had dysfunction of all organs at baseline and were therefore excluded). At 28 days, 16 of 40 patients (40%) treated with AT died versus 22 of 41 (54%) with placebo [absolute reduction, 14%; odds ratio (95% confidence interval), 0.58 (0.24–1.39)]. In patients receiving AT, a significantly increased bleeding incidence was observed (any bleeding, 8 of 40 (20.0%) for AT group vs 1/41 (2.4%) for placebo group; P < 0.015).

CONCLUSIONS: Data from this post hoc analysis confirm an increased bleeding risk seen with AT treatment in these patients. When given early in severe sepsis, though statistically not significant, absolute risk reductions with AT of 21% and 14% for organ failure and mortality, respectively, indicate a potential for treatment benefit in selected sepsis patients. This observation may have implications for continuing sepsis trials with AT that focus on reduced patient heterogeneity.

	Introduction

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Since microvascular dysfunction may be the key to the development of multiple organ failure in sepsis, the microcirculation should be a key therapeutic target.1 Adequate and early fluid resuscitation and cardiovascular support improve outcomes from septic shock,2 presumably by improving microcirculatory flow and tissue perfusion. A mortality benefit was demonstrated when activated protein C (APC) was administered to humans in the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study.3 Of note in the PROWESS study, patients with severe sepsis were treated early after onset of organ failure (within 48 h); the subgroup of patients at high risk [Acute Physiology and Chronic Health Evaluation (APACHE) II >25 or multiple organ failure] derived significant treatment benefit in terms of 28-day mortality, the study's primary end-point.3 In contrast to APC, administration in patients with severe sepsis of antithrombin (AT), another endogenous anticoagulant that successfully corrected experimental microvascular dysfunction,4,5 failed to reduce 28-day mortality in the KyberSept study.6 As early administration of AT (e.g., within 48 h) was not required according to the KyberSept study protocol, recruitment of too many patients at later stages of the disease may have prevented demonstration of the clinical efficacy of AT.7

For the KyberSept study, a single US study site recruited 81 patients with severe sepsis who were almost exclusively in the early phase of their disease, i.e., AT was administered within 48 h after the onset of organ failure. Study results for a group of patients such as these are unavailable for the entire population of the KyberSept trial and are, therefore, reported here from this single site. The beneficial effects of AT would suggest that future trials could focus more on early sepsis.

	METHODS

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Patients
The KyberSept study was a double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis.6,7 There were 2314 enrolled patients in the intention-to-treat population who were randomized into two equal groups of 1157 to receive either IV high-dose AT (30,000 IU over four days) or placebo (1% human albumin). Inclusion and exclusion criteria are described in detail in the original publication of the study.6 The protocol was approved by the institutional review board and informed consent was obtained for all patients.

Patients admitted to the intensive care unit (ICU) at the University of Oklahoma and Oklahoma City Veterans Affairs Medical Center were considered for study enrolment only when presenting with severe sepsis within 24 h after recognition of organ failure onset. Although this approach was not mandated by the protocol, it was used because of concern that the "6-h window," as planned by the study, could allow patients who have remained in severe sepsis without qualifying within the early phase to then meet criteria at a later phase, when the chances of the drug to be effective are reduced. This single study site recruited the most patients of all US participating centers, 81 randomized patients. It provides the opportunity to study, in more detail, the efficacy and safety of high-dose AT in severe sepsis when given early. The time from onset of first organ failure was monitored.

The inclusion criteria were divided into major and minor. Mandatory criteria were clinical evidence of infection, rectal temperature >38.5 or <35.5°C and a white blood cell count of >10,000/mm³ or <3500/mm³. Minor criteria were tachycardia of >100 bpm, tachypnea of >24 breaths/min or requirement for mechanical ventilation secondary to sepsis, platelet count <100,000/mm³, lactic acidosis higher than 2.2 mmol/L, urine output of <20 mL/h nonresponsive to fluid replacement, and shock, defined by the requirement for vasopressor or a systolic blood pressure of <90 mm Hg despite aggressive fluid replacement. Patients were included in the study if they met all three mandatory criteria and at least three of the minor criteria. All six criteria had to be present within a time window of 6 h before the infusion. The details of exclusion criteria can be found in the original Kybersept trial.6

The case record file of the KyberSept study was also expanded at the Oklahoma study site, in that additional morbidity variables were documented. To track organ failure after the onset of sepsis, we choose simple, easy to follow, noncontroversial criteria believed to be secondary to sepsis. Organ failure criteria definitions were chosen as follows: (renal—increase in the creatinine to twice baseline or urine output of <400 mL/d; hepatic-increase in the bilirubin level to twice baseline or to >3 mg/L; hematology—a decrease in the platelet count to <100,000 believed to be secondary to sepsis and associated with an increase of the prothrombin time and/or partial thromboplastin time; respiratory-requirement for mechanical ventilation; cardiovascular—requirement for any vasopressor to maintain arterial blood pressure). Furthermore, the time period from ICU admission to study enrollment and the time period between first organ failure and study inclusion were monitored. The occurrence of new organ dysfunction within 7 days was assessed according to the Logistic Organ Dysfunction score as reported.6 In the KyberSept study, the Simplified Acute Physiology Score (SAPS) II was used.6 In addition, the APACHE II score was calculated for patients of the Oklahoma site using standard methodology. Safety variables, including bleeding, were defined as in the KyberSept study.6

Statistical Analyses
A stratified Mantel-Haenszel test or Fisher's exact test for the intent-to-treat population or the subgroups, respectively, and 95% confidence intervals for the treatment effect (risk ratio AT/placebo) were calculated; (see the KyberSept publication for details6). Landmark mortality data were assessed between treatment groups by Mantel-Haenszel-tests stratified for the severity of the disease by SAPS II, customized for sepsis.8,9 Subgroup findings for mortality underwent multifactorial logistic regression and were tested for significant interaction with the treatment group. The percentage of patients with bleeding events was compared with Fisher's exact tests (two-sided), odds ratios, and the 95% confidence intervals between treatment groups. Calculations were performed with SAS 8.0 under Windows. Five patients (6.3%) who did not receive study drug within 48 h after onset of organ failure, were not excluded from this posthoc subgroup analysis in order not to alter the single center's random selection of patients originally enrolled.

Statistical analyses were exploratory; resulting P values were not corrected for multiplicity. All tests with a two-sided P value <0.05 were reported as nominally significant; P values <0.1 were reported as trend.

	RESULTS

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Disposition and Baseline Patient Characteristics
Forty-one patients were enrolled in the placebo group and 40 patients in the AT group. There were no relevant differences in patient demographics and baseline characteristics between the two groups (Table 1). APACHE II score, number of organ failures, and average per person organ failures did not differ between the two groups. The mean APACHE II score before drug administration was 25. Seventy-two patients (89%) received full course therapy (4 days or until death) as per protocol. The mean ± sd SAPS score on admission was 53.7 ± 15.4 (placebo: 52.5, AT III: 54.9).

Eighty percent (n = 65) of the patients received study drug within 24 h of onset of severe sepsis and 94% (n = 76) received drug within 48 h of onset of severe sepsis. Sixty-two of the 81 patients (77%) received prophylactic heparin therapy concomitantly with study drug and 67 of 81 (83%) received heparin during the study period. The dosage of heparin was at the currently accepted level of 5000 Units of heparin twice daily or equivalent in low molecular weight heparin (LMWH) with a majority receiving LMWH.

The mean ± sd AT plasma level at baseline was similar between the placebo and the AT group (69%±18% and 65%±26% (P = 0.45), respectively). Fifteen patients in the placebo group and 24 AT patients presented with AT plasma levels below 70%. AT plasma levels increased to a mean of 197% in patients receiving AT (P < 0.001) whereas it decreased to a mean of 66% in patients receiving placebo.

Efficacy
Overall mortality analysis at 28 days showed a better survival for patients who received AT; 15 of 40 patients (38%) in the AT group died versus 21 of 41 (52%) patients in the placebo group [odds ratio (95% confidence interval), 0.57 (0.23–1.38); stratified by SAPS II strata, 0.54 (0.22–1.32)]. At 90 days, the mortality rate difference was similar [AT, 20/40 (50%); placebo, 25/41 (61%); odds ratio 0.64 (0.26–1.55)]. The Kaplan–Meier estimates of survival are given in Figure 1.

View larger version (9K): [in this window] [in a new window]   Figure 1. Kaplan–Meier estimates of survival among 40 patients with severe sepsis in the antithrombin group and 41 patients in the placebo group. There was no significant difference between the treatment groups in survival until 91 days (intention-to-treat analysis; P = 0.27 by the Wilcoxon's test).

A comparison between treatment groups of the incidence of new organ dysfunction as described in the Logistic Organ Dysfunction score is presented in Table 2. Nine of 40 subjects in the AT group (22.5%) had new organ dysfunction during the first 7 days after start of study treatment which was not present at baseline compared with 17 of 41 subjects (41.5%) in the placebo group (change in risk: –45.7% (–72.5% to +7.2%); P = 0.096 with two-sided Fisher's exact test; P = 0.07 with ² test, unadjusted). Excluding two subjects who suffered from dysfunction of all organs at baseline, nine of 40 subjects in the AT group (22.5%) had a new organ dysfunction during the first 7 days after start of study treatment which was not present at baseline compared with 17 of 39 subjects (43.6%) in the placebo group (P = 0.058; change in risk: –48.4% (–73.8% to +1.6%); P = 0.058 with two-sided Fisher's exact test; P = 0.046 with ² test, unadjusted).

Safety
The most important adverse event was bleeding (Table 3). Again, 77% of our patients were receiving concomitant heparin (or LMWH). Four of 40 patients (10%) in the AT group presented with major bleeding in contrast to 1 of 41 patients (2%) in the placebo group (P = 0.2). Eight of 40 patients (20%) in the AT group experienced some bleeding compared with 1 of 41 patient (2%) in the placebo group (P = 0.015). Other adverse events were equally distributed between the placebo and AT groups.

	DISCUSSION

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In this study of adult patients with severe sepsis and a high risk of death, no significant difference was seen in mortality between the placebo and the AT groups. As the subgroup of 81 patients was small, the observed absolute mortality difference was 14% at 28 days. The response to AT (Table 2) may suggest the efficacy of AT given early in sepsis if the finding is confirmed in a larger trial. This is also suggested by a significant decrease in the incidence of new organ failure on day 7 for patients treated with AT as compared with placebo. This is further corroborated by a difference, again not statistically significant, in the ICU-free days and the days on the ventilators (data not shown) that are "surrogates" for improvement in organ dysfunction. Thus, our data do not oppose the hypothesis that AT may exert beneficial effects in severe sepsis when administered in appropriate study populations.7,10,11

The study protocol of the KyberSept trial allowed inclusion of patients when six symptoms of severe sepsis were present in a given patient within a 6-h window. This, however, did not exclude enrolment at a later stage of the disease for patients who had five of the signs or symptoms of severe sepsis already present for some time before the 6-h window, during which the sixth criterium had to be fulfilled for inclusion into the study and subsequent administration of study drug.6 It was only after the KyberSept trial had been completed that it became evident how patients with severe sepsis might derive benefit from early treatment.1–3,7 Sepsis is due to the disruption of homeostasis induced by microcirculatory dysfunction, disturbed tissue perfusion, organ failure, and death.1 This pathophysiological concept favors early therapeutic intervention before irreversible damage occurs.

Most patients in the present KyberSept subgroup were enrolled within the first 24 h after admission to the ICU and received the study drug within 48 h after the first organ failure. Our report is the first to present data on the efficacy of AT when given early in unselected randomized patients with severe sepsis. Previously, only PROWESS patients with severe sepsis were treated with APC early, within 48 h after onset of organ failure, and the subgroup of patients at high risk (APACHE II >25 or multiple organ failure) derived significant treatment benefit in terms of 28-day mortality.3 In postsurgical patients with severe sepsis, AT administration prevented the development of organ failure12,13 which may have been due, in part, to the inclusion of patients in their early phase of disease.

This KyberSept site did not enroll a sufficient number of patients to yield a precise estimate of the effect of AT in patients with sepsis and a high risk of death. In the population of patients enrolled with a predicted mortality between 30% and 60%, the KyberSept trial demonstrated significantly reduced mortalities at days 56 and 90, according to a recently published post hoc subgroup analysis.10 Our current analysis, even though without statistically significant efficacy results, agrees with the hypothesis that selection of high-risk patients may well be associated with clinically meaningful treatment benefit with AT because our placebo group mortality was 54%. Of course, this needs to be confirmed in a newly designed, prospective, randomized, controlled trial.

In the KyberSept study, the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the AT group (37.8%) than in the placebo group (43.6%) (P = 0.08); this trend became significant after 90 days (n = 686; 44.9% for AT group vs 52.5% for placebo group; P = 0.03).6 In patients receiving concomitant heparin, significant treatment benefits with AT were still seen when the predicted mortality was between 30% and 60%.10 In most of the patients of the present analysis (85%), prophylactic heparin was given concomitantly with study drug (Table 1).

The main limitations of the present study are that it comprises only 81 patients with severe sepsis and early administration of AT and that it is a posthoc, nonpredetermined analysis from a single center. The original study used stratified randomization according to the center. Although the aim is interesting and definite end-points were used, the study suffers from inadequate sample size. Under-powered, subgroup analyses are often undertaken to investigate the consistency of the trial conclusions among different subpopulations defined by each of several baseline patient characteristics. Overall in the Kybersept trial, no treatment effect was found for the primary outcome, 28-day mortality. The effect of high-dose AT relative to placebo on the risk of death and organ failure was further analyzed for consistency in subgroups either predefined in the study protocol (concomitant heparin administration, disease severity) or selected post hoc because of new scientific developments related to the disease and the drug under study (role of coagulation in severe sepsis; mechanisms of action of AT). The conclusions of these analyses were that the results of the KyberSept trial are inconsistent. However, both prespecified and post hoc subgroup analyses are subject to inflated false positive rates arising from multiple testing. KyberSept investigators had therefore avoided prespecifying too many subgroup analyses. This addition of one further post hoc analysis on the subgroup of patients with early sepsis was motivated by recent findings demonstrating the potential for greater benefit in severe sepsis patients when drug intervention is made early.

Because subgroup analyses can provide valuable information when properly planned, reported, and interpreted, we wanted to report our findings that (i) confirm safety issues of high-dose AT in a consistent manner (i.e., bleeding), and (ii) support the hypothesis that enrolment of too many patients in a later phase of their severe sepsis might have contributed to apparent inconsistencies in the KyberSept findings.

Even in this small cohort of patients, the increased bleeding incidence in the treated patients is of serious concern and, therefore, should be thoroughly discussed. AT has anticoagulant effects that result in increased bleeding episodes in patients treated with this drug.6,9,10 In the present study, serious bleeding events occurred in 2% of patients who received placebo and in 10% of patients who received AT. These rates of serious bleeding events are similar to those found in the KyberSept study (in patients who received heparin, 23.8% for AT group vs 13.5% for placebo group).6 Bleeding events involving the central nervous system are of particular concern among patients receiving anticoagulant therapies, but they did not occur with increased frequency among patients treated with AT in the present study. Such results confirm that bleeding events occur in patients treated with AT but that the increased incidence in severe bleeding is low in critically-ill patients with sepsis already at risk for serious bleeding.

From observations in clinical sepsis trials, it has been suggested that inexperienced trial sites may differ from experienced sites with regard to study outcome. The 28-day mortality of the first 509 patients with severe sepsis and a low risk of death enrolled in the ADDRESS trial was 14.5% with placebo and 22.3% with APC as compared with subsequent patients, 17.7% with placebo and 17.5% with APC in the subsequent 2104 patients, respectively (P = 0.04).14 Even if entry criteria are designed to be simple, the complexity of diagnosing and managing severe sepsis in patients and the variability inpatient care despite standardization are likely to introduce uncontrolled variables. It is possible that a reduced number of such uncontrolled factors in our single site study contributed to identifying the potential effects of AT.

Three studies on various subgroups of the large KyberSept clinical trial database have been published, one focusing on disease severity defined by SAPS II score10 and the other on the effects of coadministration of prophylactic heparin on the study drug,15 both predefined in the study protocol. There was one additional study concerning the role of disseminated intravascular coagulation on AT effects in the subgroup of patients not receiving heparin concomitantly.12 A fourth brief report compared disease severities in the KyberSept and PROWESS populations, respectively.16 In the current analysis, for the first time, data are presented on patients receiving high-dose AT or placebo in a randomized fashion that were exclusively in the early phase of sepsis.

In conclusion, enrolment into the KyberSept study of patients with severe sepsis and a high risk of death early after the onset of organ failure resulted in no significant efficacy; however, a trend toward a reduced rate of additional organ failure and mortality was seen in those receiving AT, despite administration of concomitant heparin in a majority of patients. The main concern of this conclusion is that because differences are insignificant, more conservative conclusions could be drawn. The relative contributions to study outcome of early study enrolment and high disease severity cannot be precisely defined because of the low number of patients. However, this study suggests that in future trials on the role of AT treatment in severe sepsis, particular focus could be on patient selection early after disease onset, with a correction of microcirculatory disturbance as the therapeutic target. Hypothesis-generating subgroup analyses of AT therapy in sepsis encourage continuation of the clinical development program for this interesting endogenous anticoagulant protein.

	Footnotes

 
Accepted for publication June 23, 2008.

Supported by CSL Behring GmbH, Marburg, Germany.

All authors participated as investigators in the KyberSept trial. C.J.W. has received honorarium for speaking from CSL Behring and served as principal investigator of a grant from CSL Behring to the Medical University of Innsbruck. A.E. and G.T.K. have no conflict of interest to declare.

	REFERENCES

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1. Vincent JL, De Backer D. Microvascular dysfunction as a cause of organ dysfunction in severe sepsis. Crit Care 2005;9(suppl 4): S9–S12[Web of Science][Medline]
2. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368–77[Abstract/Free Full Text]
3. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709[Abstract/Free Full Text]
4. Hoffmann JN, Vollmar B, Laschke MW, Fertmann JM, Jauch KW, Menger MD. Microcirculatory alterations in ischemia-reperfusion injury and sepsis: effects of activated protein C and thrombin inhibition. Crit Care 2005;9(suppl 4):S33–S37[Web of Science][Medline]
5. Hoffmann JN, Vollmar B, Romisch J, Inthorn D, Schildberg FW, Menger MD. Antithrombin effects on endotoxin-induced microcirculatory disorders are mediated mainly by its interaction with microvascular endothelium. Crit Care Med 2002;30:218–25[Web of Science][Medline]
6. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM; KyberSept Trial Study Group. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001;286:1869–78[Abstract/Free Full Text]
7. LaRosa SP, Opal SM. Tissue factor pathway inhibitor and antithrombin trial results. Crit Care Clin 2005;21:433–48[Web of Science][Medline]
8. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993;270:2957–63[Abstract/Free Full Text]
9. Le Gall JR, Lemeshow S, Leleu G, Klar J, Huillard J, Rue M, Teres D, Artigas A. Customized probability models for early severe sepsis in adult intensive care patients. Intensive Care Unit Scoring Group. JAMA 1995;273:644–50[Abstract/Free Full Text]
10. Wiedermann CJ, Hoffmann JN, Juers M, Ostermann H, Kienast J, Briegel J, Strauss R, Keinecke H-O, Warren BL, Opal SM, for the KyberSept investigators. High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit Care Med 2006;34:285–92[Web of Science][Medline]
11. Kienast J, Juers M, Wiedermann CJ, Hoffmann JN, Ostermann H, Strauss R, Keinecke H-O, Warren BL, Opal SM, for the KyberSept investigators. Treatment effects of highdose antithrombin III without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost 2006;4:90–7[Web of Science][Medline]
12. Hoffmann JN, Muhlbayer D, Jochum M, Inthorn D. Effect of long-term and high-dose antithrombin supplementation on coagulation and fibrinolysis in patients with severe sepsis. Crit Care Med 2004;32:1851–9[Web of Science][Medline]
13. Inthorn D, Hoffmann JN, Hartl WH, Muhlbayer D, Jochum M. Antithrombin III supplementation in severe sepsis: beneficial effects on organ dysfunction. Shock 1997;8:328–34[Web of Science][Medline]
14. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL; Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353:1332–41[Abstract/Free Full Text]
15. Hoffmann JN, Wiedermann CJ, Juers M, Ostermann H, Kienast J, Briegel J, Strauss R, Warren BL, Opal SM; KyberSept investigators. Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin. Thromb Haemost 2006;95:850–6[Web of Science][Medline]
16. Wiedermann CJ, Keinecke HO, Jürs M, Opal SM. Baseline severity of sepsis in subjects of the prowess and the Kybersept clinical trials on endogenous anticoagulants. Shock 2006; 25:657–8[Web of Science][Medline]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Eid, A. Articles by Kinasewitz, G. T. Search for Related Content PubMed PubMed Citation Articles by Eid, A. Articles by Kinasewitz, G. T. Related Collections Critical Care Coagulation Inflammation