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Antithrombin concentrate use in sepsis‐associated disseminated intravascular coagulation: re‐evaluation of a ‘pendulum effect’ drug using a nationwide database

2018; Elsevier BV; Volume: 16; Issue: 3 Linguagem: Inglês

10.1111/jth.13948

1538-7933

Takashi Tagami,

Hemodynamic Monitoring and Therapy

SummaryThere are four systematic reviews and meta‐analyses of trials of antithrombin use for sepsis or critically ill patients published to date with conflicting results. The two studies that showed positive results used data only from septic patients who were also diagnosed with disseminated intravascular coagulation (DIC), whereas the two studies showing negative results included data from all septic and/or critically ill patients in their analyses. We believe that the underlying diseases of the study population must be as homogeneous as possible when evaluating treatment efficacy for sepsis‐associated DIC. We published two large‐scale antithrombin studies of sepsis‐associated DIC using a Japanese nationwide database. The above‐mentioned DIC studies reported significant associations between antithrombin use and better 28‐day mortality in both populations (DIC‐associated with severe pneumonia, n = 9075; and with severe abdominal sepsis, n = 2164). Now is the time to initiate multinational antithrombin trials exclusively among sepsis‐associated DIC patients. There are four systematic reviews and meta‐analyses of trials of antithrombin use for sepsis or critically ill patients published to date with conflicting results. The two studies that showed positive results used data only from septic patients who were also diagnosed with disseminated intravascular coagulation (DIC), whereas the two studies showing negative results included data from all septic and/or critically ill patients in their analyses. We believe that the underlying diseases of the study population must be as homogeneous as possible when evaluating treatment efficacy for sepsis‐associated DIC. We published two large‐scale antithrombin studies of sepsis‐associated DIC using a Japanese nationwide database. The above‐mentioned DIC studies reported significant associations between antithrombin use and better 28‐day mortality in both populations (DIC‐associated with severe pneumonia, n = 9075; and with severe abdominal sepsis, n = 2164). Now is the time to initiate multinational antithrombin trials exclusively among sepsis‐associated DIC patients. Sepsis‐associated disseminated intravascular coagulation (DIC) is characterized by reduced levels of endogenous coagulation inhibitors, including antithrombin. A previous study suggested that marked reductions in serum antithrombin levels are associated with unfavorable outcomes in septic patients 1.Mesters R.M. Mannucci P.M. Coppola R. Keller T. Ostermann H. Kienast J. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients.Blood. 1996; 88: 881-6Crossref PubMed Google Scholar. Thus, antithrombin supplementation as an adjunct therapy in sepsis‐associated DIC can be regarded as rational and has been evaluated with positive results in the 1990s 2.Fourrier F. Chopin C. Huart J.J. Runge I. Caron C. Goudemand J. Double‐blind, placebo‐controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation.Chest. 1993; 104: 882-8Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar. However, the KyberSept trial 3.Warren B.L. Eid A. Singer P. Pillay S.S. Carl P. Novak I. Chalupa P. Atherstone A. Penzes I. Kubler A. Knaub S. Keinecke H.O. Heinrichs H. Schindel F. Juers M. Bone R.C. Opal S.M. Caring for the critically ill patient. High‐dose antithrombin III in severe sepsis: a randomized controlled trial.JAMA. 2001; 286: 1869-78Crossref PubMed Scopus (1137) Google Scholar, the largest antithrombin trial for severe sepsis, failed to prove any beneficial effects of administering a 'high dose' of antithrombin (30 000 IU per 4 days) on mortality. This then resulted in the so‐called 'pendulum effect' 4.Vincent J.L. We should abandon randomized controlled trials in the intensive care unit.Crit Care Med. 2010; 38: S534-8Crossref PubMed Scopus (143) Google Scholar (whereby a positive or beneficial effect of an intervention is followed by a later study that demonstrates no effect, or worse, a negative effect) and condemnation of the clinical use of antithrombin for sepsis‐associated DIC patients in almost all countries except Japan. Two systematic reviews and meta‐analyses of trials for antithrombin use were published in 2006 and 2007 (2000s) 5.Wiedermann C.J. Kaneider N.C. A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis.Blood Coagul Fibrinolysis. 2006; 17: 521-6Crossref PubMed Scopus (65) Google Scholar, 6.Afshari A. Wetterslev J. Brok J. Moller A. Antithrombin III in critically ill patients: systematic review with meta‐analysis and trial sequential analysis.BMJ. 2007; 335: 1248-51Crossref PubMed Scopus (76) Google Scholar, and two additional studies were recently published in 2016 7.Umemura Y. Yamakawa K. Ogura H. Yuhara H. Fujimi S. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta‐analysis of randomized controlled trials.J Thromb Haemost. 2016; 14: 518-30Crossref PubMed Scopus (115) Google Scholar, 8.Allingstrup M. Wetterslev J. Ravn F.B. Moller A.M. Afshari A. Antithrombin III for critically ill patients: a systematic review with meta‐analysis and trial sequential analysis.Intensive Care Med. 2016; 42: 505-20Crossref PubMed Scopus (68) Google Scholar. Interestingly, conflicting results were noted within the 2000s and the 2016 publications. Why did this happen? Studies reporting positive results from both the 2000s and 2016 publications included data only from septic patients who were diagnosed with DIC 5.Wiedermann C.J. Kaneider N.C. A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis.Blood Coagul Fibrinolysis. 2006; 17: 521-6Crossref PubMed Scopus (65) Google Scholar, 7.Umemura Y. Yamakawa K. Ogura H. Yuhara H. Fujimi S. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta‐analysis of randomized controlled trials.J Thromb Haemost. 2016; 14: 518-30Crossref PubMed Scopus (115) Google Scholar. Studies reporting negative results included data from all sepsis and/or critically ill patients in their analyses 6.Afshari A. Wetterslev J. Brok J. Moller A. Antithrombin III in critically ill patients: systematic review with meta‐analysis and trial sequential analysis.BMJ. 2007; 335: 1248-51Crossref PubMed Scopus (76) Google Scholar, 8.Allingstrup M. Wetterslev J. Ravn F.B. Moller A.M. Afshari A. Antithrombin III for critically ill patients: a systematic review with meta‐analysis and trial sequential analysis.Intensive Care Med. 2016; 42: 505-20Crossref PubMed Scopus (68) Google Scholar. It is therefore rational to rethink, from a pathophysiological and pharmacological perspective, that antithrombin is not a 'magical drug' for all sepsis and/or critically ill patients. Antithrombin is a drug that should only be administered to treat DIC in patients whose plasma antithrombin levels are (at least) below the normal level. There is currently no 'one‐size‐fits‐all' magical drug that does not have any adverse effects, particularly when administered to critically ill patients. However, almost all of the recent guidelines, except Japanese guidelines, do not support the use of antithrombin for sepsis/sepsis‐associated DIC patients 9.Oda S. Aibiki M. Ikeda T. Imaizumi H. Endo S. Ochiai R. Kotani J. Shime N. Nishida O. Noguchi T. Matsuda N. Hirasawa H. Sepsis Registry Committee of The Japanese Society of Intensive Care MedicineThe Japanese guidelines for the management of sepsis.J Intensive Care. 2014; 2: 55Crossref PubMed Scopus (62) Google Scholar. The Surviving Sepsis Campaign guidelines and recent DIC guidelines from the UK and Italy are against the use of a 'high dose' of antithrombin for sepsis‐associated DIC patients 10.Rhodes A. Evans L.E. Alhazzani W. Levy M.M. Antonelli M. Ferrer R. Kumar A. Sevransky J.E. Sprung C.L. Nunnally M.E. Rochwerg B. Rubenfeld G.D. Angus D.C. Annane D. Beale R.J. Bellinghan G.J. Bernard G.R. Chiche J.D. Coopersmith C. De Backer D.P. et al.Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.Intensive Care Med. 2017; 43: 304-77Crossref PubMed Scopus (3706) Google Scholar. In contrast, as per the Japanese guidelines, a 'supplemental dose' of antithrombin (1500 IU per day) has been recommended for sepsis‐associated DIC patients whose plasma antithrombin III levels are below 70% 9.Oda S. Aibiki M. Ikeda T. Imaizumi H. Endo S. Ochiai R. Kotani J. Shime N. Nishida O. Noguchi T. Matsuda N. Hirasawa H. Sepsis Registry Committee of The Japanese Society of Intensive Care MedicineThe Japanese guidelines for the management of sepsis.J Intensive Care. 2014; 2: 55Crossref PubMed Scopus (62) Google Scholar. Importantly, this supplemental dose is far lower than the dosage given in the KyberSept trial (i.e. 30 000 IU per 4 days) 3.Warren B.L. Eid A. Singer P. Pillay S.S. Carl P. Novak I. Chalupa P. Atherstone A. Penzes I. Kubler A. Knaub S. Keinecke H.O. Heinrichs H. Schindel F. Juers M. Bone R.C. Opal S.M. Caring for the critically ill patient. High‐dose antithrombin III in severe sepsis: a randomized controlled trial.JAMA. 2001; 286: 1869-78Crossref PubMed Scopus (1137) Google Scholar. The supplemental dose of antithrombin administration for sepsis‐associated DIC was developed originally in Japan, and its 'unique evolution' resulted in increasing isolation from the world of evidence‐based medicine 11.Tagami T. Matsui H. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study: reply.J Thromb Haemost. 2015; 13: 680-2Crossref PubMed Scopus (2) Google Scholar. The Japanese Ministry of Health, Labor and Welfare has approved an antithrombin dose of 1500 IU per day (up to 3000 IU per day only in cases of surgical emergency) for patients with DIC whose antithrombin activity is less than 70%. However, this value was set not on the basis of any scientific evidence, but rather according to the suggestions from the authority or experts approximately 30 years ago, and the use of this phrase is continued in the medication package insert (package leaflet) of antithrombin even currently, without appropriate scientific validation. Therefore, for better or for worse, antithrombin administration is thus restricted only to DIC patients diagnosed based on both clinical and laboratory evidence in Japan (i.e. not for patients with sepsis in general). To accurately diagnose DIC, several DIC definitions have been developed, validated and revised in Japan 12.Gando S. Iba T. Eguchi Y. Ohtomo Y. Okamoto K. Koseki K. Mayumi T. Murata A. Ikeda T. Ishikura H. Ueyama M. Ogura H. Kushimoto S. Saitoh D. Endo S. Shimazaki S. Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Study GroupA multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria.Crit Care Med. 2006; 34: 625-31Crossref PubMed Scopus (387) Google Scholar. The Japanese guidelines recommend the evaluation of plasma antithrombin levels before and after antithrombin administration. Gando and colleagues 13.Gando S. Saitoh D. Ishikura H. Ueyama M. Otomo Y. Oda S. Kushimoto S. Tanjoh K. Mayumi T. Ikeda T. Iba T. Eguchi Y. Okamoto K. Ogura H. Koseki K. Sakamoto Y. Takayama Y. Shirai K. Takasu O. Inoue Y. Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group for the JAAM DIC Antithrombin TrialA randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis.Crit Care. 2013; 17: R297Crossref PubMed Scopus (108) Google Scholar reported a randomized trial of this 'supplemental dose' of antithrombin in sepsis‐associated DIC patients. Although the above‐mentioned study failed to prove a reduction in short‐term mortality with statistical significance (n = 60), antithrombin (1500 IU per day) was reported to improve DIC scores, thereby increasing the recovery rate without any risk of bleeding in sepsis‐associated DIC patients. Finally, the unique evolution resulted in the discovery of genetic recombinant antithrombin, antithrombin gamma (Acoalan®, Kyowa Hakko Kirin Co., Tokyo, Japan), which has been commercially available in Japan since September 2015 (http://www.kyowa-kirin.com/news_releases/2017/pdf/e20170914_01.pdf). Several similar 'unique evolution' drugs, including antithrombin administration for DIC 14.Tagami T. Matsui H. Moroe Y. Fukuda R. Shibata A. Tanaka C. Unemoto K. Fushimi K. Yasunaga H. Antithrombin use and 28‐day in‐hospital mortality among severe‐burn patients: an observational nationwide study.Ann Intensive Care. 2017; 7: 18Crossref PubMed Scopus (10) Google Scholar, 15.Tagami T. Matsui H. Fushimi K. Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis.Thromb Haemost. 2015; 114: 537-45Crossref PubMed Scopus (32) Google Scholar, 16.Tagami T. Matsui H. Horiguchi H. Fushimi K. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study.J Thromb Haemost. 2014; 12: 1470-9Crossref PubMed Scopus (111) Google Scholar, recombinant human soluble thrombomodulin for DIC 17.Tagami T. Matsui H. Horiguchi H. Fushimi K. Yasunaga H. Recombinant human soluble thrombomodulin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study.J Thromb Haemost. 2015; 13: 31-40Crossref PubMed Scopus (49) Google Scholar and intravenous immunoglobulin for sepsis 18.Tagami T. Matsui H. Fushimi K. Yasunaga H. Intravenous immunoglobulin and mortality in pneumonia patients with septic shock: an observational nationwide study.Clin Infect Dis. 2015; 61: 385-92Crossref PubMed Scopus (41) Google Scholar, were previously evaluated using the Japanese Diagnosis Procedure Combination (DPC) database. Several experimental studies have suggested that these drugs are pharmacologically appropriate for the treatment of each pathophysiological condition. However, clinical data about their effectiveness are limited and their uses have been internationally condemned after the 'pendulum effect'. Most of the treatments listed above are not recommended by international guidelines for severe sepsis 10.Rhodes A. Evans L.E. Alhazzani W. Levy M.M. Antonelli M. Ferrer R. Kumar A. Sevransky J.E. Sprung C.L. Nunnally M.E. Rochwerg B. Rubenfeld G.D. Angus D.C. Annane D. Beale R.J. Bellinghan G.J. Bernard G.R. Chiche J.D. Coopersmith C. De Backer D.P. et al.Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.Intensive Care Med. 2017; 43: 304-77Crossref PubMed Scopus (3706) Google Scholar, and the drugs are not even commercially available for use in clinical settings, except in a few countries. Although the Japanese DPC database is similar to the US National Inpatient Sample, the DPC database has unique advantages. For example, comorbidities present on admission are clearly distinguished from complications that occur following admission. In addition, the DPC database contains data about the types of treatment that patients received (i.e. medications, drip infusions, and several procedures, including surgeries) and the starting dates and duration of each treatment during hospitalization. These data allowed us to clearly define inclusion and exclusion criteria in our studies 11.Tagami T. Matsui H. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study: reply.J Thromb Haemost. 2015; 13: 680-2Crossref PubMed Scopus (2) Google Scholar, 14.Tagami T. Matsui H. Moroe Y. Fukuda R. Shibata A. Tanaka C. Unemoto K. Fushimi K. Yasunaga H. Antithrombin use and 28‐day in‐hospital mortality among severe‐burn patients: an observational nationwide study.Ann Intensive Care. 2017; 7: 18Crossref PubMed Scopus (10) Google Scholar, 15.Tagami T. Matsui H. Fushimi K. Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis.Thromb Haemost. 2015; 114: 537-45Crossref PubMed Scopus (32) Google Scholar, 16.Tagami T. Matsui H. Horiguchi H. Fushimi K. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study.J Thromb Haemost. 2014; 12: 1470-9Crossref PubMed Scopus (111) Google Scholar, 17.Tagami T. Matsui H. Horiguchi H. Fushimi K. Yasunaga H. Recombinant human soluble thrombomodulin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study.J Thromb Haemost. 2015; 13: 31-40Crossref PubMed Scopus (49) Google Scholar, 18.Tagami T. Matsui H. Fushimi K. Yasunaga H. Intravenous immunoglobulin and mortality in pneumonia patients with septic shock: an observational nationwide study.Clin Infect Dis. 2015; 61: 385-92Crossref PubMed Scopus (41) Google Scholar. We believe that the DPC database is, at least currently, the best available nationwide database for evaluating the effect of treatments that are used only in Japan. We thus tried to report these domestic data from Japan, regardless of the results (positive or negative results) and our (investigators') own particular preferences 11.Tagami T. Matsui H. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study: reply.J Thromb Haemost. 2015; 13: 680-2Crossref PubMed Scopus (2) Google Scholar, 14.Tagami T. Matsui H. Moroe Y. Fukuda R. Shibata A. Tanaka C. Unemoto K. Fushimi K. Yasunaga H. Antithrombin use and 28‐day in‐hospital mortality among severe‐burn patients: an observational nationwide study.Ann Intensive Care. 2017; 7: 18Crossref PubMed Scopus (10) Google Scholar, 15.Tagami T. Matsui H. Fushimi K. Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis.Thromb Haemost. 2015; 114: 537-45Crossref PubMed Scopus (32) Google Scholar, 16.Tagami T. Matsui H. Horiguchi H. Fushimi K. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study.J Thromb Haemost. 2014; 12: 1470-9Crossref PubMed Scopus (111) Google Scholar, 17.Tagami T. Matsui H. Horiguchi H. Fushimi K. Yasunaga H. Recombinant human soluble thrombomodulin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study.J Thromb Haemost. 2015; 13: 31-40Crossref PubMed Scopus (49) Google Scholar, 18.Tagami T. Matsui H. Fushimi K. Yasunaga H. Intravenous immunoglobulin and mortality in pneumonia patients with septic shock: an observational nationwide study.Clin Infect Dis. 2015; 61: 385-92Crossref PubMed Scopus (41) Google Scholar. Among the three DPC studies of the 'supplemental dose' of antithrombin for DIC patients 14.Tagami T. Matsui H. Moroe Y. Fukuda R. Shibata A. Tanaka C. Unemoto K. Fushimi K. Yasunaga H. Antithrombin use and 28‐day in‐hospital mortality among severe‐burn patients: an observational nationwide study.Ann Intensive Care. 2017; 7: 18Crossref PubMed Scopus (10) Google Scholar, 15.Tagami T. Matsui H. Fushimi K. Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis.Thromb Haemost. 2015; 114: 537-45Crossref PubMed Scopus (32) Google Scholar, 16.Tagami T. Matsui H. Horiguchi H. Fushimi K. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study.J Thromb Haemost. 2014; 12: 1470-9Crossref PubMed Scopus (111) Google Scholar, we first evaluated 9075 patients with severe pneumonia and sepsis‐associated DIC 16.Tagami T. Matsui H. Horiguchi H. Fushimi K. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study.J Thromb Haemost. 2014; 12: 1470-9Crossref PubMed Scopus (111) Google Scholar. A significant association was found between 28‐day mortality and antithrombin use using propensity‐score matched analysis (antithrombin use vs. control group: 40.6% vs. 44.2%, P = 0.02). Instrumental variable analysis showed that the receipt of antithrombin was associated with a 9.9% (95% confidence interval [CI], 3.5–16.3) reduction in 28‐day mortality. Second, we evaluated 2164 patients with abdominal sepsis and DIC (mechanically ventilated septic shock DIC patient after emergency surgery for perforation of the lower intestinal tract) 15.Tagami T. Matsui H. Fushimi K. Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis.Thromb Haemost. 2015; 114: 537-45Crossref PubMed Scopus (32) Google Scholar. A significant difference was found between the antithrombin and the control group using propensity‐score matched analysis (27.6% vs. 19.9%; difference, 7.7%; 95% CI, 2.5–12.9). Instrumental variable analysis showed that the receipt of antithrombin was associated with a 6.5% (95% CI, 0.05–13.0) reduction in 28‐day mortality. The data from 3223 patients with severe burns (burn index >10) that were recently published 14.Tagami T. Matsui H. Moroe Y. Fukuda R. Shibata A. Tanaka C. Unemoto K. Fushimi K. Yasunaga H. Antithrombin use and 28‐day in‐hospital mortality among severe‐burn patients: an observational nationwide study.Ann Intensive Care. 2017; 7: 18Crossref PubMed Scopus (10) Google Scholar reported that antithrombin use may improve 28‐day survival and increase ventilator‐free days. There are several organs that can cause infection and sepsis‐associated DIC. The lungs and abdomen are the most common sites of infection resulting in sepsis 19.Angus D.C. van der Poll T. Severe sepsis and septic shock.N Engl J Med. 2013; 369: 840-51Crossref PubMed Scopus (1848) Google Scholar. However, the pathophysiology and mortality rate of DIC are different among various underlying diseases 19.Angus D.C. van der Poll T. Severe sepsis and septic shock.N Engl J Med. 2013; 369: 840-51Crossref PubMed Scopus (1848) Google Scholar. The host and inflammatory (as well as anti‐inflammatory) response mechanisms to sepsis are highly variable, depending on the initial site of infection, causative organisms, patterns of acute organ dysfunction, underlying health status of the patient, and whether or not the infection source was controlled surgically 19.Angus D.C. van der Poll T. Severe sepsis and septic shock.N Engl J Med. 2013; 369: 840-51Crossref PubMed Scopus (1848) Google Scholar. Therefore, it is believed that when evaluating treatment efficacy for sepsis‐associated DIC, the underlying diseases must be as homogeneous as possible. We cannot draw any robust conclusions yet regarding the effect of antithrombin for DIC patients in general, at least from our retrospective analysis 14.Tagami T. Matsui H. Moroe Y. Fukuda R. Shibata A. Tanaka C. Unemoto K. Fushimi K. Yasunaga H. Antithrombin use and 28‐day in‐hospital mortality among severe‐burn patients: an observational nationwide study.Ann Intensive Care. 2017; 7: 18Crossref PubMed Scopus (10) Google Scholar, 15.Tagami T. Matsui H. Fushimi K. Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis.Thromb Haemost. 2015; 114: 537-45Crossref PubMed Scopus (32) Google Scholar, 16.Tagami T. Matsui H. Horiguchi H. Fushimi K. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study.J Thromb Haemost. 2014; 12: 1470-9Crossref PubMed Scopus (111) Google Scholar. Moreover, DPC data studies have important limitations. The DPC database does not include data regarding the coagulation status (e.g. DIC score, antithrombin activity, platelet count, and D‐dimer or fibrinogen level), vital signs or cause of death. These data may be possible important unmeasured confounders for the analyses. There is no doubt that randomized control trials are the reference standard to evaluate the effectiveness of particular interventions. However, in randomized control trials with a heterogeneous population of critically ill patients, some interventions may be beneficial to some patients but harmful to others, leading to an overall negative trial result 4.Vincent J.L. We should abandon randomized controlled trials in the intensive care unit.Crit Care Med. 2010; 38: S534-8Crossref PubMed Scopus (143) Google Scholar. On the other hand, analyzing well‐designed large clinical databases of observational data with sophisticated statistical techniques may result in accurate determination of the effects of the treatment. The homogeneity of the study participants suggests that the beneficial effects of the treatment are more likely to be detected 20.Zhang Z. Ni H. Xu X. Observational studies using propensity score analysis underestimated the effect sizes in critical care medicine.J Clin Epidemiol. 2014; 67: 932-9Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar. In studies assessing antithrombin administration, it is necessary to include plasma antithrombin levels among the inclusion criteria along with a definite diagnosis of DIC to maintain homogeneity of the study participants. The results of our previous studies 15.Tagami T. Matsui H. Fushimi K. Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis.Thromb Haemost. 2015; 114: 537-45Crossref PubMed Scopus (32) Google Scholar, 16.Tagami T. Matsui H. Horiguchi H. Fushimi K. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study.J Thromb Haemost. 2014; 12: 1470-9Crossref PubMed Scopus (111) Google Scholar support the published hypothesis that the supplemental dose of antithrombin is effective in the treatment of patients with sepsis‐associated DIC. However, the jury is still out 11.Tagami T. Matsui H. Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study: reply.J Thromb Haemost. 2015; 13: 680-2Crossref PubMed Scopus (2) Google Scholar. We therefore believe that now is the time to work out the evidence for the domestic 'unique evolution' drug, now is the time to find out the optimal antithrombin activity level and dose of antithrombin concentrate internationally, and now is the time to start multinational antithrombin trials exclusively conducted among sepsis‐associated DIC patients. The author states that he has no conflict of interest.