COVID-19 and anticoagulation: evidence from a meta-analysis of randomized controlled trials

We appreciate the interest and insightful commentary (1) on our meta-analysis investigating anticoagulant therapy in coronavirus disease 2019 (COVID-19) patients. Our findings (2) indicate that anticoagulant therapy is associated with reduced all-cause mortality and thrombotic risk in non-severe COVID-19 cases. Furthermore, therapeutic-dose anticoagulation may be considered for both non-severe and severe COVID-19 patients to mitigate thrombotic complications, though this intervention appears correlated with an elevated risk of bleeding events. The concerns raised by de Mello Gonzaga et al. were about clinical heterogeneity within the non-severe COVID-19 category.

In this study, we focused on the severity of the patient’s condition rather than whether hospitalization was required or the specific criteria for hospitalization. Because it is important to note that hospitalization standards may vary across different countries and regions in clinical practice. In addition, in the context of COVID-19 pandemic, the accessibility to health care resources and differences in public quarantine policies further affect the decision of hospitalization, especially for non-severe patients. In contrast, disease severity based on World Health Organization (WHO) guidelines was more subjective, which appears to be a more reasonable choice to reduce the intrinsic heterogeneity between groups.

Regarding the DeNucci (3) study on nebulized heparin, existing literature has established the therapeutic potential of nebulized heparin in COVID-19, acute respiratory distress syndrome (ARDS), and severe pneumonia patients (4-6). Consequently, we deemed it methodologically justified to incorporate the nebulized heparin study into our meta-analysis of anticoagulant therapies.

To elucidate the differential efficacy of anticoagulants based on hospitalization status, we conducted a sensitivity analysis. Given the significant heterogeneity in hospitalization status distribution across the 20 included studies, we stratified patients into two cohorts: non-hospitalized (or discharged) and hospitalized. The analysis revealed that anticoagulation did not significantly reduce all-cause mortality in non-hospitalized patients [relative risk (RR): 0.58, 95% confidence interval (CI): 0.27–1.26, P=0.17], whereas a significant mortality reduction was observed in hospitalized patients (RR: 0.33, 95% CI: 0.11–0.96, P=0.04). Notably, anticoagulation therapy was associated with reduced thrombotic incidence in non-hospitalized patients (RR: 0.36, 95% CI: 0.15–0.84, P=0.02). Regarding bleeding risk, our findings did not demonstrate significant anticoagulant-associated bleeding events in either cohort (non-hospitalized: RR: 1.53, 95% CI: 0.43–5.37, P=0.51; hospitalized: RR: 1.34, 95% CI: 0.25–7.10, P=0.73).

In dose-response analyses, only one study (7) included non-hospitalized patients, prompting our focus on the hospitalized population. Therapeutic-dose anticoagulation showed no mortality benefit compared with prophylactic dose (RR: 1.02, 95% CI: 0.93–1.11, P=0.72) but demonstrated significant thrombotic risk reduction (RR: 0.63, 95% CI: 0.47–0.85, P=0.002) with increased bleeding risk (RR: 1.98, 95% CI: 1.38–2.82; P<0.001). In addition, stratification by disease severity—both before and after accounting for hospitalization status—did not significantly alter these outcomes.

Acknowledging the respective strengths and limitations of these classification approaches, we emphasize the necessity for large-scale, multicenter, parallel-group randomized controlled trials to definitively establish the efficacy, safety profile, and optimal dosing strategies of anticoagulation therapy across diverse patient populations.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article did not undergo external peer review.

Funding: This study was supported by the National Natural Science Foundation of China [Nos. 82130001 (to Y.S.), 82272243 (to Y.S.), and 82200090 (to Y.W.)], the Shanghai Municipal Science and Technology Major Project [No. ZD2021CY001 (to Y.S.)], the National Key Research and Development Program of China [No. 2024YFC3044400 (to Y.S.)], the R&D Program of Guangzhou National Laboratory [No. GZNL2024A02003 (to Y.S.)], the Construction of Multi-Disciplinary Treatment System for Severe Pneumonia [No. W2020-013 (to Y.S.)], the Shanghai Three-Year Action Plan to Strengthen the Construction of Public Health System [No. GWVI-11.1-18 (to Y.S.)], the Science and Technology Commission of Shanghai Municipality [No. 22Y11900800 (to Y.S.)] and the Shanghai Municipal Key Clinical Specialty [No. shslczdzk02201 (to Y.S.)].

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-407/coif). Y.W. receives the National Natural Science Foundation of China (No. 82200090). Y.S. receives the National Natural Science Foundation of China (Nos. 82130001 and 82272243), the Shanghai Municipal Science and Technology Major Project (No. ZD2021CY001), the National Key Research and Development Program of China (No. 2024YFC3044400), the R&D Program of Guangzhou National Laboratory (No. GZNL2024A02003), the Construction of Multi-Disciplinary Treatment System for Severe Pneumonia (No. W2020-013), the Shanghai Three-Year Action Plan to Strengthen the Construction of Public Health System (No. GWVI-11.1-18), the Science and Technology Commission of Shanghai Municipality (No. 22Y11900800), and the Shanghai Municipal Key Clinical Specialty (No. shslczdzk02201). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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