Impact of early heparin therapy on outcomes in patients with solid malignancy associated sepsis: a marginal structural model causal analyse

Jia-Jia Huang; Ji-Zhen Cai; Zhi-Peng Zhou; Yan Liu; Zhen-Jia Yang; Da-Zheng Li; Yu-Hua Chen; Ying-Yi Luan; Yong-Ming Yao; Ming Wu

doi:10.3389/fphar.2023.1281235

Impact of early heparin therapy on outcomes in patients with solid malignancy associated sepsis: a marginal structural model causal analyse

Front Pharmacol. 2023 Dec 4:14:1281235. doi: 10.3389/fphar.2023.1281235. eCollection 2023.

Authors

Jia-Jia Huang^#^{1

2}, Ji-Zhen Cai^#³, Zhi-Peng Zhou¹, Yan Liu^{1

4}, Zhen-Jia Yang¹, Da-Zheng Li¹, Yu-Hua Chen^{1

5}, Ying-Yi Luan⁶, Yong-Ming Yao⁷, Ming Wu^{1

4}

Affiliations

¹ Department of Infection and Critical Care Medicine, Shenzhen Second People's Hospital and First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China.
² Intensive Care Unit, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
³ Department of Critical Care Medicine and Hematology, Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Nosocomial Infection Prevention and Control, Shenzhen Second People's Hospital, Shenzhen, China.
⁵ Department of Emergency Medicine, Shenzhen Second People's Hospital, Shenzhen, China.
⁶ Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
⁷ Trauma Research Center, Medical Innovation Research Department and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China.

^# Contributed equally.

Abstract

Background: Previous studies documented that heparin can inhibit the invasion and metastasis of tumors, but its role on outcomes in patients with solid malignancy complicated sepsis remains unclear. Methods: A retrospective cohort study was conducted in critically ill patients with solid malignancy associated sepsis from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was intensive care unit (ICU) mortality, secondary outcomes were thrombosis and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), cox proportional hazards model, stratification analysis and E-value were used to account for baseline differences, time-varying confounding and unmeasured variables. Results: A total of 1,512 patients with solid malignancy complicated sepsis were enrolled, of which 683 in the heparin group with intensive care unit mortality, thrombosis rate and hospital mortality were 9.7%, 5.4%, 16.1%, and 829 in the non-heparin group with ICU mortality, thrombosis rate and hospital mortality were 14.6%, 12.5%, 22.6%. Similar results were observed on outcomes for patients with PSM (ICU mortality hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41-0.92), thrombosis rate (HR 0.42, 95% confidence interval 0.26-0.68); hospital mortality HR 0.70, 95% CI 0.50-0.99). marginal structural Cox model further reinforced the efficacy of heparin in reducing ICU mortality (HR 0.48, 95% CI 0.34-0.68). Logistic regression and Cox regression model showed heparin use also markedly reduced thrombosis (HR 0.42; 95% CI 0.26-0.68; p < 0.001) and hospital mortality (HR 0.70; 95% CI 0.50-0.99; p = 0.043). Stratification analysis with the MSCM showed an effect only those with digestive system cancer (HR 0.33, 95% CI 0.16-0.69). Conclusion: Early heparin therapy improved outcomes in critically ill patients with solid malignancy complicated sepsis. These results are evident especially in those with digestive system cancer. A prospective randomized controlled study should be designed to further assess the relevant findings.

Keywords: heparin; mortality; sepsis; solid malignancy; thrombosis.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the Sanming Project of Medicine in Shenzhen (SZSM20162011), Medical Science and Technology Research Foundation of Guangdong Province (No. A2023354), Science, Technology, and Innovation Commission of Shenzhen Municipality (JCYJ20190806163603504) and Shenzhen Second People’s Hospital Clinical Research Fund of Guangdong Province High-level Hospital Construction Projects (20203357014, 2023xgyj3357001,2023yjlcyj022).