Antithrombin III in patients admitted to intensive care units: a multicenter observational study.

Abstract

The administration of antithrombin III (ATIII) is useful in patients with congenital deficiency, but evidence for the other therapeutic indications of this drug is still uncertain. In Italy, the use of ATIII is very common in intensive care units (ICUs). For this reason we undertook an observational study to determine the pattern of use of ATIII in ICUs and to assess the outcome of patients given this treatment.
From 20 May to 20 July 2001 all consecutive patients admitted to ICUs in 20 Italian hospitals and treated with ATIII were enrolled. The following information was recorded from each patient: congenital deficiency, indication for use of ATIII, daily dose and duration of ATIII treatment, outcome of hospitalization (alive or dead). The outcome data of our observational study were compared with those reported in previously published randomized controlled trials (RCTs).
Two hundred and sixteen patients were enrolled in the study. The clinical indications for using ATIII were sepsis (25.9%), disseminated intravascular coagulation (23.1%), and other clinical conditions (46.8%). At the end of the study, 65.3% of the patients were alive, 24.5% died and 10.2% were still in the hospital. Among the patients with sepsis (n = 56), 19 died during the observation period (33.9%; 95% confidence interval 22.1-47.5%).
Our study described the pattern of use of ATIII in Italian hospitals and provided information on the outcome of the subgroup treated with sepsis. A meta-analysis of current data from RCTs, together with our findings, indicates that there is no sound basis for using this drug in ICU patients with sepsis.

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Available online http://ccforum.com/content/6/5/447
Research
Antithrombin III in patients admitted to intensive care units:
a multicenter observational study
Andrea Messori1, Franca Vacca2, Monica Vaiani2, Sabrina Trippoli2, and the Gruppo di Studio
sull’antitrombina III*
1Coordinator, Laboratorio SIFO di Farmacoeconomia, c/o Drug Information Center, Azienda Ospedaliera Careggi, Florence, Italy
2Researcher, Laboratorio SIFO di Farmacoeconomia, c/o Drug Information Center, Azienda Ospedaliera Careggi, Florence, Italy
Correspondence: Andrea Messori, md3439@mclink.it
Introduction
Antithrombin III (ATIII) is a recognized treatment for patients
with congenital ATIII deficiency [1–5] (see also the approval
of this indication by the Food and Drug Administration); in
contrast, the evidence supporting its use for other clinical
indications is uncertain [6–10].
In Italian hospitals this drug is widely used in patients admit-
ted to intensive care units (ICUs), who are generally given
ATIII for the treatment of sepsis or disseminated intravascular
coagulation (DIC). The approval of ATIII by the Italian Ministry
of Health was granted nearly 10 years ago (before the pro-
found reform of the Drug Regulatory Agency made by the
ATIII = antithrombin III; CI = confidence interval; DIC = disseminated intravascular coagulation; ICU, intensive care unit; RCT = randomized con-
trolled trial.
*See Appendix 1
Abstract
Introduction The administration of antithrombin III (ATIII) is useful in patients with congenital
deficiency, but evidence for the other therapeutic indications of this drug is still uncertain. In Italy, the
use of ATIII is very common in intensive care units (ICUs). For this reason we undertook an
observational study to determine the pattern of use of ATIII in ICUs and to assess the outcome of
patients given this treatment.
Methods From 20 May to 20 July 2001 all consecutive patients admitted to ICUs in 20 Italian
hospitals and treated with ATIII were enrolled. The following information was recorded from each
patient: congenital deficiency, indication for use of ATIII, daily dose and duration of ATIII treatment,
outcome of hospitalization (alive or dead). The outcome data of our observational study were
compared with those reported in previously published randomized controlled trials (RCTs).
Results Two hundred and sixteen patients were enrolled in the study. The clinical indications for using
ATIII were sepsis (25.9%), disseminated intravascular coagulation (23.1%), and other clinical
conditions (46.8%). At the end of the study, 65.3% of the patients were alive, 24.5% died and 10.2%
were still in the hospital. Among the patients with sepsis (n = 56), 19 died during the observation
period (33.9%; 95% confidence interval 22.1–47.5%).
Discussion Our study described the pattern of use of ATIII in Italian hospitals and provided
information on the outcome of the subgroup treated with sepsis. A meta-analysis of current data from
RCTs, together with our findings, indicates that there is no sound basis for using this drug in ICU
patients with sepsis.
Keywords antithrombin III, disseminated intravascular coagulation, sepsis, septic shock
Received: 8 January 2002
Revisions requested: 4 March 2002
Revisions received: 18 May 2002
Accepted: 20 June 2002
Published: 24 July 2002
Critical Care 2002, 6:447-451
This article is online at http://ccforum.com/content/6/5/447
© 2002 Messori et al., licensee BioMed Central Ltd
(Print ISSN 1364-8535; Online ISSN 1466-609X)

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Critical Care October 2002 Vol 6 No 5Messori et al.
Italian Ministry of Health in 1993) and has remained unchanged
since then. This approval of ATIII was rather generic and
included ‘congenital deficiency of ATIII and all clinical condi-
tions that can cause an acquired deficiency of ATIII’.
Three small randomized studies [7–9] and one large interna-
tional trial [10] assessed the effectiveness of ATIII in sepsis, but
none of these trials found a significant benefit in terms of
reduced morbidity or mortality. As regards congenital deficiency,
the effectiveness of ATIII is fairly well documented [1–5], but
these patients are rare. The other clinical indications (such as
acute thrombosis or thromboembolism, prevention of DIC in
hepatic coma, and treatment of bleeding episodes in cirrhosis)
are supported by a small series of very preliminary studies (see,
for example, the Drugdex databank, CD-ROM Drugdex, volume
110; Micromedex, Englewood, Colorado, USA).
To achieve a better definition of the current use of ATIII in
Italian hospitals and to generate naturalistic data (based on
routine practice) about the outcome of this treatment, we
undertook a multicenter observational study.
Methods
Design of the study and aims
The study was based on a multicenter observational design.
From 20 May to 20 July 2001 all consecutive patients admit-
ted to ICUs in 20 Italian hospitals and treated with ATIII were
enrolled in the study. The study had the following aims: (1)
surveying the use of ATIII in patients admitted to ICUs; (2)
determining the outcome of patients treated with ATIII; and
(3) comparing the results obtained from our observational
study with those previously found in the randomized con-
trolled trials (RCTs).
A meta-analysis was also conducted to summarize the infor-
mation deriving from four RCTs [7–10] that studied the effec-
tiveness of ATIII in sepsis.
Data collection
The following information was recorded from each patient
enrolled in the study: (1) demographic characteristics (age,
sex, weight); (2) congenital deficiency (y/n); (3) baseline ATIII
level; (4) ward of first admission in the hospital; (5) clinical
indication for using ATIII (sepsis or DIC or any other clinical
condition); (6) daily dose and duration of treatment with ATIII;
(7) outcome of hospitalization (alive or dead); and (8) concur-
rent administration of antibiotics and/or heparin.
Analysis
The information collected from each patient was analyzed by
standard descriptive statistics. In the subgroup of patients
with sepsis, the in-hospital mortality rate observed in our
study was compared with that previously reported by the four
RCTs. All rates were presented together with their 95% con-
fidence interval (CI), which was calculated by using Equa-
tions 1.26 and 1.27 of Fleiss [11].
Results
The overall number of patients who were admitted to ICUs
during the study period was 1648. Of these patients, 216
(13%) were enrolled in our study. The characteristics of these
216 patients are presented in Table 1.
The clinical indication for using ATIII was sepsis (n = 56), DIC
(n = 50), or other (n = 101). Table 1 also reports separate
information for the subgroup of 56 patients treated for sepsis.
The duration of ATIII therapy did not differ at levels of statisti-
cal significance between patients treated for different clinical
indications (P = 0.57 according to an analysis of variance).
The daily dose of ATIII showed a difference between sepsis
and other indications (Table 1).
Table 2 reports the outcome of hospitalization according to
clinical indication. With regard to the use of ATIII in patients
with sepsis, Figure 1 shows the percentage mortality rate
(with 95% CI) observed in our study, together with the rates
found in four previous studies [7–10].
Subgroup analyses within the patient cohort of our study did
not identify any relationship between mortality and patient
characteristics. The administration of heparin, which Warren
et al. [10] found to have some implications for outcome, did
not influence mortality in our patient series: mortality was
19.6% in the 107 patients who received heparin, compared
with 30.5% in the 95 patients who did not receive this drug
(P = 0.10) by Fisher’s exact test; mortality was 28.6% in the
28 patients with sepsis who received heparin, compared with
42.3% in the 26 patients with sepsis who did not receive this
drug (P = 0.39).
Discussion
The main scientific value of our observational and prospective
study lies in its naturalistic design; the population of patients
that we studied was in fact drawn from the everyday practice
of more than 20 hospitals and was intentionally free from spe-
cific exclusion criteria.
In interpreting our outcome data, one disadvantage is that the
group treated with ATIII was not compared with any reference
group observed prospectively within our research; neither did
we include any retrospective control group not treated with
the drug. However, historical retrospective controls would
have raised profound problems of matching the retrospective
data with the prospective ones. A prospective enrollment of
controls not treated with ATIII was not feasible because the
therapeutic policy of the ICUs involved in our study was to
administer ATIII to virtually all patients with a diagnosis of
sepsis or DIC.
Regardless of our statistical indexes, a ‘first-look’ comparison
between the data on sepsis produced by the previous RCTs
(including four treatment groups and four control groups) and

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those observed in our naturalistic study indicates a complete
overlap of the various survival rates and of their respective
95% CIs. This qualitative impression (Figure 1) is in agree-
ment with the meta-analysis shown in Figure 2 (see
Appendix 2 for details of its methodology).
This meta-analysis gave the following results: summary
odds ratio 0.98; 95% CI 0.83–1.15, P = 0.80; χ2for het-
erogeneity 1.86; 3 degrees of freedom; P = 0.60. In this
meta-analysis, the large-scale trial by Warren et al. [10]
outweighed the other three small RCTs in that Warren’s
trial included 93% of the overall cohort of the four RCTs. In
the light of the above data, there seems to be no clinical
benefit in administering ATIII to critical patients with
sepsis; in this context, one crucial point is that the most
recent large-scale trial gave very clear results and was neg-
ative. The other clinical indications reported in our patients’
series were more difficult to interpret because of the nearly
complete lack of previous controlled studies exploring
these therapeutic issues.
There has been a lively debate in the literature on the relative
merits of observational studies and RCTs in providing useful
evidence of clinical effectiveness [12–14]. Although the great
majority of researchers stick to the concept that RCTs are the
gold standard, common sense suggests that having informa-
tion both from RCTs and from observational studies is better
than having information from RCTs only. In this framework,
our study advances knowledge about the use of ATIII in criti-
cal patients.
Available online http://ccforum.com/content/6/5/447
Table 1
Characteristics of the 216 patients enrolled in our observational study and of the subgroup of 56 patients treated for sepsis
Overall group of patients Patient subgroup with sepsis
Patients’ characteristics
n
Characteristics
n
Characteristics
Age (years)208 62.0 ± 17.25261.8 ± 16.7
Sex (male, female)211 146, 6552 38, 14
Body weight (kg)16275.5 ± 9.248 77.9 ± 16.2
ATIII level at baseline (%)20957.4 ± 18.2 55 54.3 ± 14.9
Congenital deficiency 1801 (0.5%)47 0 (0%)
Ward of admission (surgery, other)204 111, 935127, 24
Administration of antibiotics 199179 (83%) 5350 (89%)
Administration of heparin 202107 (50%) 5428 (50%)
Daily dose of ATIII (units per patient)1951758 ± 1092 471988 ± 981
Duration of administration of ATIII (days)1953.1 ± 4.1 473.5 ± 2.6
n is the number of evaluable patients. Where errors are shown these are SDs. The daily doses of ATIII according to the clinical indications were as
follows: sepsis (n = 47), 1988 ± 981 units/day; disseminated intravascular coagulation (n = 46), 1857 ± 967 units/day; other indications (n = 94),
1518 ± 1000 units/day. A one-way analysis of variance showed that these values were significantly different (F = 4.1; 2 and 184 degrees of
freedom; P = 0.02); post-hoc tests showed that the only difference that reached significance was between sepsis and other indications (P = 0.03).
Table 2
Relationship between clinical indication for the use of ATIII and outcome of hospitalization
Outcome of hospitalization
Clinical indication
n
AliveDead Still in hospital at the end of the study
Sepsis5631 (55.4%) 19 (33.9%)6 (10.7%)
DIC50 30 (60%)16 (32%) 4 (8%)
Any other clinical condition101 75 (74.3%)16 (15.8%) 10 (9.9%)
Not reported95 (55.6%)2 (22.2%) 2 (22.2%)
Total 216141 (65.3%) 53 (24.5%)22 (10.2%)
Percentages, which should be read horizontally, indicate which of the three outcomes was found in the various patient subgroups.
DIC, disseminated intravascular coagulation.

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In conclusion, our findings based on an observational
prospective study and on an updated meta-analysis of the
previous RCTs do not support the use of this drug in ICU
patients with sepsis.
Competing interests
In 2001 our research group received a grant from Eli-Lilly
(Italy) to conduct an original study on factors influencing
length of stay in critical patients with sepsis. In Italy, anti-
thrombin III is marketed by Aventis-Behring and by Baxter.
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Critical Care October 2002 Vol 6 No 5 Messori et al.
Key messages
•Antithrombin III (ATIII) is a recognized treatment for
patients with congenital ATIII deficiency; in contrast,
the evidence supporting its use for other clinical
indications is uncertain
•In Italian hospitals this drug is widely used in patients
admitted to intensive care units (ICUs), who are
generally given ATIII for the treatment of sepsis or
disseminated intravascular coagulation
•Three small randomized studies and one large
international trialhave assessed the effectiveness of
ATIII in sepsis, but none of these trials has found a
significant benefit in terms of reduced morbidity or
mortality
• Our findings, based on an observational prospective
study and on an updated meta-analysis of the previous
randomized controlled trials, do not support the use of
this drug in ICU patients without congenital deficiency
Figure 2
Comparison of death rates between patients given ATIII and patients
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meta-analysis are denoted by dots and by a diamond, respectively;
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vertical dotted line represents the identity line. From top to bottom,
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al. [9], and Fourrier et al. [7]; the bottom dataset is our meta-analysis.
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[8], 31 of 50 versus 33 of 48; Warren et al. [10], 450 of 1157 versus
448 of 1157.
0 1 2 3
Odds ratio
ATIII betterPlacebo better
Figure 1
Percentage mortality rate (with 95% CI) of patients with sepsis:
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[8]; 2001, Warren et al. [10] and our study.
0
10
20
30
40
50
60
70
80
90
1992 1993 1994 1995 1996 1997 1998 19992000 2001 20022003
Publication year
Percent death rate (with 95%CI)

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Appendix 1: Gruppo di Studio
sull’antitrombina III (The Antithrombin Study
Group)
The Antithrombin Study Group includes the study coordina-
tors (A Messori, F Vacca, M Vaiani, S Trippoli, Laboratorio di
Farmacoeconomia, c/o Azienda Ospedaliera Careggi,
Firenze) and a total of 51 participants. The names and
addresses of the participants involved in the project were the
following (all located in Italy): R Banfi, M Cecchi, E Cini, D
Dupuis, T Falai, R Fornaini, A Ipponi, ML Migliaccio, F
Pelagotti, L Rabatti, I Ruffino, R Silvano, E Tendi (Firenze, four
hospitals); P Becagli, M Monciatti (Empoli); B Bozzone, R
Casullo, F Cattel, S Pardossi, R Passera, S Stecca, U Taglia-
ferro (Torino, two hospitals); P Di Bartolomeo, T Faggiano, M
Lattarulo (Bari); N Caboni, A Cannas (Cagliari); A Plescia, M
Sorci (Rimini); L Bonistalli, M Puliti (Prato); B Ciammitti, M
Costantini, F Mammini (Terni); L De Cicco, G Mazzaferro
(Napoli); P Marrone, R Tetamo (Palermo); P Beneduce, MG
Celeste, P Fiorani, S Galeassi, G Guaglianone, A Pecere, L
Ragni (Roma, two hospitals); SM Germinario (Andria); O
Basadonna, L Todesco (Camposampiero, Padova); R Calle-
gari, M Pegoraro (Asolo); E Lamura (Ancona).
Appendix 2: Methodology of the meta-analysis
A MedLine search (PubMed, http://www.ncbi.nlm.nih.gov/
entrez/query.fcgi) was performed to cover the period from
January 1980 to November 2001. The search was limited to
the studies published in English and was based on four index
terms combined with the following Boolean syntax: “antithrom-
bin III” AND (sepsis OR septic shock OR “disseminated
intravascular coagulation”). This search was supplemented by
examining the Drugdex databank (CD-ROM Drugdex, volume
110; Micromedex, Englewood, Colorado, USA).
Eligible studies were included if they met the following criteria:
patients were admitted to an ICU; randomized design; diagno-
sis of sepsis, septic shock or DIC; assessment of survival. The
odds ratio was used as the main index to assess the treatment
effect within each trial and to generate the overall results of
the meta-analysis. The calculation of the summary odds ratios
was based on a random-effect model [15,16]. Heterogeneity
was assessed as described previously [17].
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