Introduction 1 2 3 4 5 6 7 8 9 10 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 (DIC). The approval of ATIII by the Italian Ministry of Health was granted nearly 10 years ago (before the profound reform of the Drug Regulatory Agency made by the 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 conditions that can cause an acquired deficiency of ATIII'. 7 8 9 10 1 2 3 4 5 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 admitted 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 controlled trials (RCTs). 7 8 9 10 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) concurrent administration of antibiotics and/or heparin. Analysis 11 Results 1 n n n 1 P 1 2 1 7 8 9 10 et al 10 P P 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 specific 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. 1 2 P 2 P et al 10 12 13 14 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. 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 trial have 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. 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. Appendix 1: Gruppo di Studio sull'antitrombina III (The Antithrombin Study Group) The Antithrombin Study Group includes the study coordinators (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 Tagliaferro (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  15 16 17 Abbreviations ATIII = antithrombin III; CI = confidence interval; DIC = disseminated intravascular coagulation; ICU, intensive care unit; RCT = randomized controlled trial.