Critical appraisal of the inclusion criteria in: “Anticoagulant therapy in adult with COVID-19: a systematic review and meta-analysis of randomized controlled trial” for non-severe patients

We read with great interest the meta-analysis by Zhou et al. on anticoagulant therapy in patients with coronavirus disease 2019 (COVID-19) (1), particularly the findings presented in Fig. 2A, which evaluated all-cause mortality in non-severe COVID-19 patients. However, we are concerned that certain methodological aspects may compromise the extrapolation of these results to the milder COVID-19 outpatients. Specifically, the inclusion of hospitalized patients and those receiving post-discharge prophylaxis, alongside exclusively outpatient cases, in the non-severe COVID-19 category introduces significant clinical heterogeneity. This approach combines patients with distinct clinical severity profiles, evaluating them as if they were similar, which, in our assessment, makes the generalization of the results potentially hazardous. In this regard, we believe the inclusion of the studies by DeNucci et al. (2), Ramacciotti et al. (3), and Toshner et al. (4) which exclusively evaluated hospitalized patients, along with studies by Ananworanich et al. (5), Barco et al. (6) and Cools et al. (7), which exclusively evaluated outpatient cases in the analysis of mortality for this specific patient group is inappropriate for several reasons.

The DeNucci study

The inclusion criteria for the DeNucci et al. study required hospitalization and a Modified Ordinal Scale (MOC) score of at least 3. According to the World Health Organization (WHO) Ordinal Scale (8), a score of 3 corresponds to symptomatic disease requiring assistance and scores 4 and 5 to moderate disease requiring hospitalization. Moreover, all recorded deaths occurred in patients with MOC scores of 4 or 5. Additionally, the intervention—nebulized heparin—is not routinely used in clinical practice, further limiting the study’s relevance to non-severe outpatient disease.

The Ramacciotti and Toshner studies

Both Ramacciotti et al. and Toshner et al.’s studies evaluated hospitalized patients receiving post-discharge prophylaxis. In Ramacciotti et al.’s study, for example, even patients admitted to intensive care units (ICUs) were included. This cohort represents a population with greater disease severity and higher baseline risks of thrombotic events and mortality compared to non-severe COVID-19 outpatients. Similarly, Toshner et al.’s study focused on hospitalized patients, discharged with prophylactic anticoagulation, further limiting its generalizability to never hospitalized patients with non-severe disease.

If we excluded these studies from the meta-analysis and grouped only the studies related to outpatient cases, we would obtain the following result:

Risk ratio: 1.04 (95% confidence interval: 0.07–16.6); P=0.98; which indicates absence of benefit from anticoagulation.

This outcome highlights the extremely low event rate in non-severe COVID-19 outpatients (0.18% in the intervention group vs. 0.17% in the control group).

We urge caution in interpreting the results of this meta-analysis regarding anticoagulation and mortality in non-severe COVID-19 patients and suggest that studies involving outpatient cases be evaluated separately from those involving hospitalized patients. The inclusion of studies involving predominantly hospitalized patients or post-discharge prophylaxis is inappropriate to inform treatment decisions for non-hospitalized COVID-19 outpatients, which represents a significant proportion of the overall cases, especially in the post vaccination era.

This approach risks overstating the benefits of anticoagulation, potentially leading to its unnecessary use in asymptomatic or mildly symptomatic outpatients, exposing them to intervention-related risks without proven benefits.

We recommend that future systematic reviews and meta-analyses in this area clearly delineate the populations under investigation, grouping in the statistical analysis studies that are truly similar regarding the population of interest, to ensure adequate clinical applicability. Such precision is critical to avoid misinterpretation and to guide evidence-based clinical practice effectively.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-21/coif). Y.B.d.M.G. works for Oncoclinicas, while V.A.Q.M. worked for Rede D’or and served as coagulation consultant to hospitals in both nonprofit and profit organizations during the pandemic. Both organizations are for-profit companies, but the authors hold no share in either institution nor other company related to anticoagulation-related drugs or laboratories. The authors have no other 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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