Recombinant human soluble thrombomodulin in patients with sepsis-associated coagulopathy (SCARLET): an updated meta-analysis
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 . 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 . 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” . The inadequate population of 22% reported in JAMA may attenuate the power to detect the effectiveness of the intervention .
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 . 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.
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.
This research did not receive any funding.
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TI has participated in advisory boards of Asahi Kasei Pharmaceuticals. The other authors declare that they have no competing interests.
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