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Critical Care

, 23:302 | Cite as

Recombinant human soluble thrombomodulin in patients with sepsis-associated coagulopathy (SCARLET): an updated meta-analysis

  • Kazuma YamakawaEmail author
  • Jerrold H. Levy
  • Toshiaki Iba
Open Access
Letter

Abbreviation

rTM

Recombinant human soluble thrombomodulin

Letter to the editor

The reported trial of recombinant human soluble thrombomodulin (rTM) in sepsis failed to show a 28-day all-cause mortality reduction [1]. Although the primary efficacy results did not support the administration of rTM, we found a positive signal in a post hoc analysis in the SCARLET trial. We also are concerned about the eligibility of patient selection possibly caused by a protocol amendment that lengthened the allowable time period from first qualifying INR until dosing as noted in the JAMA editorial [2]. In this trial, approximately 22% of subjects in the full analysis set (182/816 patients) did not fulfill the protocol-specified coagulopathy criteria (INR > 1.4 and platelet count > 30 × 109/L) when the first dose of the study drug was administered. This population was thought to have a lower grade of coagulation disorder and/or lower disease severity. We have previously shown the importance of selecting a target population for anticoagulant therapy in sepsis that should be based on two critical components that include a “coagulation disorder” and “high disease severity” [3]. The inadequate population of 22% reported in JAMA may attenuate the power to detect the effectiveness of the intervention [1].

Recently, we reported the latest systematic review and meta-analysis [4] of recombinant thrombomodulin for sepsis including SCARLET trial results that were made public in August 2018. The data of five trials enrolling 1762 patients showed that the pooled estimate on mortality of recombinant thrombomodulin use was not statistically significant (risk ratio, 0.87; 95% confidence interval, 0.74–1.03; P = 0.10; I2 = 0%). A significant limitation of our meta-analysis was the lack of full results from the SCARLET trial. We therefore performed re-analyses by replacing the SCARLET results with a subgroup analysis of the proportion who still met the coagulopathy criteria at dosing. Consequently, mortality risk was reduced by the administration of recombinant thrombomodulin (risk ratio, 0.82; 95% confidence interval, 0.69–0.98; P = 0.03; I2 = 0%) (Fig. 1).
Fig. 1

Forest plot of the comparison: rTM vs. control: all-cause mortality at 28 days. rTM, recombinant human thrombomodulin; M-H, Mantel-Haenszel; CI, confidence interval

Importantly, as a limitation mentioned by Vincent et al., post hoc analyses used in this re-analyzed meta-analysis were not planned a priori and need to be interpreted with caution. To properly implement precision medicine, a strategy of selecting the optimal target of an individual intervention is essential [5]. SCARLET is the first trial intended to examine the effects of anticoagulants in coagulopathic patients. We suggest that further trials of recombinant thrombomodulin should be performed that focus on the strictly eligible population that can potentially benefit from this therapy.

Notes

Acknowledgements

Not applicable.

Authors’ contributions

KY, JHL, and TI were responsible for the conception of the letter. All authors drafted the manuscript. All authors read and approved the final manuscript.

Funding

This research did not receive any funding.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

TI has participated in advisory boards of Asahi Kasei Pharmaceuticals. The other authors declare that they have no competing interests.

References

  1. 1.
    Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirov MY, et al. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy. JAMA. 2019;321(20):1993–2002.PubMedCrossRefGoogle Scholar
  2. 2.
    van der Poll T. Recombinant human soluble thrombomodulin in patients with sepsis-associated coagulopathy: another negative sepsis trial? JAMA. 2019;321(20):1978–80.PubMedCrossRefGoogle Scholar
  3. 3.
    Yamakawa K, Umemura Y, Hayakawa M, et al. Benefit profile of anticoagulant therapy in sepsis: a nationwide multicentre registry in Japan. Crit Care. 2016;20(1):229.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Yamakawa K, Murao S, Aihara M. Recombinant human soluble thrombomodulin in sepsis-induced coagulopathy: an updated systematic review and meta-analysis. Thromb Haemost. 2019;119(1):56–65.PubMedCrossRefGoogle Scholar
  5. 5.
    Vincent JL. The coming era of precision medicine for intensive care. Crit Care. 2017;21(Suppl 3):314.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© The Author(s). 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  1. 1.Division of Trauma and Surgical Critical CareOsaka General Medical CenterOsakaJapan
  2. 2.Department of Anesthesiology, Critical Care, and SurgeryDuke University School of MedicineDurhamUSA
  3. 3.Department of Emergency and Disaster MedicineJuntendo University Graduate School of MedicineTokyoJapan

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