682 Letters to the Editor 9 Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009; 145: 24–33. 10 Di Nisio M, Baudo F, Cosmi B, D’Angelo A, De Gasperi A, Malato A, Schiavoni M, Squizzato A, Italian Society for Thrombosis and Haemostasis. Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2012; 129: e177–84. 11 Wada H, Asakura H, Okamoto K, Iba T, Uchiyama T, Kawasugi K, Koga S, Mayumi T, Koike K, Gando S, Kushimoto S, Seki Y, Madoiwa S, Maruyama I, Yoshioka A, Japanese Society
of Thrombosis Hemostasis DICs. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res 2010; 125: 6–11. 12 Iba T, Gando S, Thachil J. Anticoagulant therapy for sepsisassociated disseminated intravascular coagulation: the view from Japan. J Thromb Haemost 2014; 12: 1010–9. 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, et al. A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis. Crit Care 2013; 17: R297.
Antithrombin or thrombomodulin administration in severe pneumonia patients with sepsis and disseminated intravascular coagulation: comment on two papers T. IBA Department of Emergency and Disaster Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan
To cite this article: Iba T. Antithrombin or thrombomodulin administration in severe pneumonia patients with sepsis and disseminated intravascular coagulation: comment on two papers. J Thromb Haemost 2015; 13: 682–3. See also 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: 31–40; 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: 1470–9 and Tagami T, Matsui H, Yasunaga H. Antithrombin or thrombomodulin administration in severe pneumonia patients with sepsis and disseminated intravascular coagulation: reply to two papers. This issue, pp 686–8.
I thoroughly enjoyed reading the research article by Tagami et al. [1], but was somewhat intrigued by the contrasting results described in this report and their recently published report in the Journal of Thrombosis and Haemostasis [2]. Both recombinant thrombomodulin and antithrombin concentrate are listed as ‘potentially recommended’ agents in the ‘Guidance for diagnosis and treatment of disseminated intravascular coagulation (DIC)’ Correspondence: Toshiaki Iba, Department of Emergency and Disaster Medicine, Graduate School of Medicine, Juntendo University, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Tel.: +81 3 3813 3111 (X: 5818) fax: +81 3 3813 5431. E-mail: [email protected] DOI: 10.1111/jth.12853 Received 22 December 2014 Manuscript handled by: M. Levi Final decision: F. R. Rosendaal, 11 January 2015
published by the Scientific and Standardization Committee (SSC) on DIC of the International Society on Thrombosis and Haemostasis (ISTH) [3]. Currently, these agents are two of the most used agents in Japan [4], and each occupies approximately 40–50% share of the market. Tagami et al. performed almost the same analyses for both anticoagulants using a nationwide administrative database and reported opposite results: the results suggested that while antithrombin concentrate was effective, recombinant thrombomodulin was not. Indeed, ‘potentially effective’ means ‘needs further evidence,’ and Tagami et al. performed propensity score matching analyses for both the agents independently almost at the same time. The results revealed that a supplement dose of antithrombin (30–60 IU kg 1 per day 9 3 days) was associated with a 28-day mortality of 40.6%, while the control group (without antithrombin) showed a 28-day mortality of 44.2%, indicating significant reduction of the mortality in the antithrombin group (P = 0.02). Subsequently, they performed the same analysis for recombinant thrombomodulin, and demonstrated that treatment with thrombomodulin did not reduce the mortality rate. The 28© 2015 International Society on Thrombosis and Haemostasis
Letters to the Editor 683
day all-cause mortality in propensity-matched cohorts was 37.6% in the thrombomodulin group vs. 37.0% in the control group, and the odds ratio was 1.01 (95% CI, 0.93–1.10). Was recombinant thrombomodulin really ineffective? Were there any occurrences that masked its efficacy? Both analyses were performed in severe pneumonia patients with DIC, but the mortality in the control group was higher in the study carried out for antithrombin. Therefore, we speculate that the result could have been influenced by differences in the disease severity. Could the difference in the sample sizes have affected the results? The propensity analysis for antithrombin created a larger number of matched cohorts (2194 pairs), while that for thrombomodulin created 1140 pairs. The larger sample size in the former analysis may have made it possible to reveal the efficacy of antithrombin. However, because the mortality rate in the treatment group was rather higher in the thrombomodulin analysis, the difference in the sample sizes might not be a rational explanation for the difference in the results. Other than the above, some reasons cited by the authors in the discussion section might also explain the results; however, my real concern is in relation to the unmeasured confounders. For example, to adjust for differences in the baseline characteristics and disease severity, a propensity score analysis based on the treatment and disease name was carried out. Nevertheless, as the authors have stated, the administrative database does not contain some essential physical data, including those on the vital signs, standard laboratory data and the results of DIC-specific coagulation tests. Although the possible variables are matched and the best way considered was taken, the severity and other important factors such as initiation timing, applied dose and duration might not have been adequately matched. In addition, I am afraid that many readers might misunderstand that antithrombin is superior to thrombomodulin as a therapeutic agent for sepsis-associated DIC. Why were the results so discrepant? Bias among physicians or institutes could be one possible explanation. The authors used hospitals’ preferences as an instrumental variable, and computed the differences in the 28-day mortality between groups treated and not treated with thrombomodulin, and found no association between the patterns of hospital use of thrombomodulin and mortality. This could be an explanation for the results of the current study, but not for the discrepant results between the antithrombin analysis and the thrombomodulin analysis. Because the selection of anticoagulants was dependent on the physicians’ or institutes’ choices, if the physicians or the institutes that preferred antithrombin showed better performance, the results would be something like this. Recently, another analysis using the administrative database failed to demonstrate the efficacy of therapy
© 2015 International Society on Thrombosis and Haemostasis
used in Japan. Endotoxin adsorption by direct hemoperfusion using a polymyxin B-immobilized fiber column has been widely applied for the treatment of septic shock in Japan. Iwagami et al. [5] reported the absence of a significant association between the use of polymyxin B hemoperfusion and 28-day mortality. Well, I do not believe that this analysis was performed adequately [6]. The Japanese administrative database system was established to implement a standardized electronic claims system, and not for the survey of epidemiological data. Thus, it does not contain the aforementioned essential data that are crucial for this type of study. Therefore, caution is needed when applying the results of analyses based on the Japanese administrative database to real clinical practice. Finally, I fully agree with their conclusion, ‘we must wait for the results of an ongoing multicenter, prospective, randomized, phase 3 trial (ClinicalTrials.gov Identifier: NCT01598831) before drawing any further conclusions’. Acknowledgement T. Iba is a member of the JSTH/DIC subcommittee. Disclosure of Conflict of Interest The author states that he has no conflict of interests. References 1 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: 31–40. 2 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: 1470–9. 3 Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, Kim HK, Nielsen JD, Dempfle CE, Levi M, Toh CH. The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost 2013; 11: 761–7. 4 Iba T, Gando S, Thachil J. Anticoagulant therapy for sepsis-associated disseminated intravascular coagulation: the view from Japan. J Thromb Haemost 2014; 12: 1010–9. 5 Iwagami M, Yasunaga H, Doi K, Horiguchi H, Fushimi K, Matsubara T, Yahagi N, Noiri E. Postoperative polymyxin B hemoperfusion and mortality in patients with abdominal septic shock: a propensity-matched analysis. Crit Care Med 2013; 42: 1187–93. 6 Hashiguchi N, Iba T. Is postoperative polymyxin B hemoperfusion for abdominal septic shock really ineffective? Crit Care Med 2014; 42: e598–9.
of Thrombosis Hemostasis DICs. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res 2010; 125: 6–11. 12 Iba T, Gando S, Thachil J. Anticoagulant therapy for sepsisassociated disseminated intravascular coagulation: the view from Japan. J Thromb Haemost 2014; 12: 1010–9. 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, et al. A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis. Crit Care 2013; 17: R297.
Antithrombin or thrombomodulin administration in severe pneumonia patients with sepsis and disseminated intravascular coagulation: comment on two papers T. IBA Department of Emergency and Disaster Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan
To cite this article: Iba T. Antithrombin or thrombomodulin administration in severe pneumonia patients with sepsis and disseminated intravascular coagulation: comment on two papers. J Thromb Haemost 2015; 13: 682–3. See also 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: 31–40; 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: 1470–9 and Tagami T, Matsui H, Yasunaga H. Antithrombin or thrombomodulin administration in severe pneumonia patients with sepsis and disseminated intravascular coagulation: reply to two papers. This issue, pp 686–8.
I thoroughly enjoyed reading the research article by Tagami et al. [1], but was somewhat intrigued by the contrasting results described in this report and their recently published report in the Journal of Thrombosis and Haemostasis [2]. Both recombinant thrombomodulin and antithrombin concentrate are listed as ‘potentially recommended’ agents in the ‘Guidance for diagnosis and treatment of disseminated intravascular coagulation (DIC)’ Correspondence: Toshiaki Iba, Department of Emergency and Disaster Medicine, Graduate School of Medicine, Juntendo University, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Tel.: +81 3 3813 3111 (X: 5818) fax: +81 3 3813 5431. E-mail: [email protected] DOI: 10.1111/jth.12853 Received 22 December 2014 Manuscript handled by: M. Levi Final decision: F. R. Rosendaal, 11 January 2015
published by the Scientific and Standardization Committee (SSC) on DIC of the International Society on Thrombosis and Haemostasis (ISTH) [3]. Currently, these agents are two of the most used agents in Japan [4], and each occupies approximately 40–50% share of the market. Tagami et al. performed almost the same analyses for both anticoagulants using a nationwide administrative database and reported opposite results: the results suggested that while antithrombin concentrate was effective, recombinant thrombomodulin was not. Indeed, ‘potentially effective’ means ‘needs further evidence,’ and Tagami et al. performed propensity score matching analyses for both the agents independently almost at the same time. The results revealed that a supplement dose of antithrombin (30–60 IU kg 1 per day 9 3 days) was associated with a 28-day mortality of 40.6%, while the control group (without antithrombin) showed a 28-day mortality of 44.2%, indicating significant reduction of the mortality in the antithrombin group (P = 0.02). Subsequently, they performed the same analysis for recombinant thrombomodulin, and demonstrated that treatment with thrombomodulin did not reduce the mortality rate. The 28© 2015 International Society on Thrombosis and Haemostasis
Letters to the Editor 683
day all-cause mortality in propensity-matched cohorts was 37.6% in the thrombomodulin group vs. 37.0% in the control group, and the odds ratio was 1.01 (95% CI, 0.93–1.10). Was recombinant thrombomodulin really ineffective? Were there any occurrences that masked its efficacy? Both analyses were performed in severe pneumonia patients with DIC, but the mortality in the control group was higher in the study carried out for antithrombin. Therefore, we speculate that the result could have been influenced by differences in the disease severity. Could the difference in the sample sizes have affected the results? The propensity analysis for antithrombin created a larger number of matched cohorts (2194 pairs), while that for thrombomodulin created 1140 pairs. The larger sample size in the former analysis may have made it possible to reveal the efficacy of antithrombin. However, because the mortality rate in the treatment group was rather higher in the thrombomodulin analysis, the difference in the sample sizes might not be a rational explanation for the difference in the results. Other than the above, some reasons cited by the authors in the discussion section might also explain the results; however, my real concern is in relation to the unmeasured confounders. For example, to adjust for differences in the baseline characteristics and disease severity, a propensity score analysis based on the treatment and disease name was carried out. Nevertheless, as the authors have stated, the administrative database does not contain some essential physical data, including those on the vital signs, standard laboratory data and the results of DIC-specific coagulation tests. Although the possible variables are matched and the best way considered was taken, the severity and other important factors such as initiation timing, applied dose and duration might not have been adequately matched. In addition, I am afraid that many readers might misunderstand that antithrombin is superior to thrombomodulin as a therapeutic agent for sepsis-associated DIC. Why were the results so discrepant? Bias among physicians or institutes could be one possible explanation. The authors used hospitals’ preferences as an instrumental variable, and computed the differences in the 28-day mortality between groups treated and not treated with thrombomodulin, and found no association between the patterns of hospital use of thrombomodulin and mortality. This could be an explanation for the results of the current study, but not for the discrepant results between the antithrombin analysis and the thrombomodulin analysis. Because the selection of anticoagulants was dependent on the physicians’ or institutes’ choices, if the physicians or the institutes that preferred antithrombin showed better performance, the results would be something like this. Recently, another analysis using the administrative database failed to demonstrate the efficacy of therapy
© 2015 International Society on Thrombosis and Haemostasis
used in Japan. Endotoxin adsorption by direct hemoperfusion using a polymyxin B-immobilized fiber column has been widely applied for the treatment of septic shock in Japan. Iwagami et al. [5] reported the absence of a significant association between the use of polymyxin B hemoperfusion and 28-day mortality. Well, I do not believe that this analysis was performed adequately [6]. The Japanese administrative database system was established to implement a standardized electronic claims system, and not for the survey of epidemiological data. Thus, it does not contain the aforementioned essential data that are crucial for this type of study. Therefore, caution is needed when applying the results of analyses based on the Japanese administrative database to real clinical practice. Finally, I fully agree with their conclusion, ‘we must wait for the results of an ongoing multicenter, prospective, randomized, phase 3 trial (ClinicalTrials.gov Identifier: NCT01598831) before drawing any further conclusions’. Acknowledgement T. Iba is a member of the JSTH/DIC subcommittee. Disclosure of Conflict of Interest The author states that he has no conflict of interests. References 1 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: 31–40. 2 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: 1470–9. 3 Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, Kim HK, Nielsen JD, Dempfle CE, Levi M, Toh CH. The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost 2013; 11: 761–7. 4 Iba T, Gando S, Thachil J. Anticoagulant therapy for sepsis-associated disseminated intravascular coagulation: the view from Japan. J Thromb Haemost 2014; 12: 1010–9. 5 Iwagami M, Yasunaga H, Doi K, Horiguchi H, Fushimi K, Matsubara T, Yahagi N, Noiri E. Postoperative polymyxin B hemoperfusion and mortality in patients with abdominal septic shock: a propensity-matched analysis. Crit Care Med 2013; 42: 1187–93. 6 Hashiguchi N, Iba T. Is postoperative polymyxin B hemoperfusion for abdominal septic shock really ineffective? Crit Care Med 2014; 42: e598–9.
