BD - Earth day 2024

Effect of Antiplatelet Therapy After Covid-19 Diagnosis: a Systematic Review With Meta-analysis and Trial Sequential Analysis

Hong Duo, Mengying Jin, Yanwei Yang, Rewaan Baheti, Yujia Feng, Zirui Fu, Yuyue Jiang, Lanzhuoying Zheng, Jing Wan, Huaqin Pan


Coronavirus disease 2019 (COVID-19) may predispose patients to thrombotic disease in the venous and arterial circulations. Based on the current debate on antiplatelet therapy in COVID-19 patients, we performed a systematic review and meta-analysis to investigate the effect of antiplatelet treatments. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science on February 1, 2023, and only included Randomized clinical trials. The study followed PRISMA guidelines and used Random-effects models to estimate the pooled percentage and its 95% CI.


Coronavirus disease 2019 (COVID-19) represents an unprecedented global threat caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. COVID-19 may predispose patients to thrombotic disease in both venous and arterial circulations, due to excessive inflammation, platelet activation, endothelial dysfunction, and stasis [2]. Critically ill COVID-19 patients are at an elevated risk of hypercoagulability and increased thrombotic risk [3]. Interactions between activated platelets and neutrophils lead to the breakdown of extracellular matrix proteins and the production of thrombin, which may be associated with disseminated intravascular coagulation (DIC) and a hypercoagulable state [4]. Early antiplatelet drugs may inhibit uncontrolled adhesion, aggregation, and platelet activation, thereby reducing the risk of severe organ dysfunction.

Materials and method

Our comprehensive study was performed in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline (S1 Table) [23]. A systematic review protocol to PROSPERO in advance (registration number: CRD42022321234) was developed and registered.


Five studies met our inclusion criteria in Fig 1 [25–29]. Characteristics of the included studies are shown in Table 1 and S4 Table. Primary outcomes and secondary outcomes are shown in Table 2. S5 and S6 Tables supplement primary outcomes and secondary outcomes. Five studies fulfilled our inclusion criteria of randomized control trials, with a combined population of 17,950 patients. 1549 patients from REMAP-CAP [25] are comparing aspirin and P2Y12 inhibitor versus no antiplatelet therapy in critically ill patients hospitalized for COVID-19; 562 patients from ACTIV-4a [26] comparing P2Y12 inhibitor versus a therapeutic dose of heparin only (usual care) in non-critically ill patients hospitalized for COVID-19; 657 patients from ACTIV-4B [27] comparing aspirin versus apixaban and placebo in symptomatic outpatients with COVID-19; 14892 patients from RECOVERY [28] comparing aspirin versus usual standard of care in patients hospitalized with COVID-19;290 patients from PACT [29] comparing clopidogrel versus no clopidogrel in critically ill patients hospitalized for COVID-19.


This systematic review and meta-analysis comprehensively assess the available evidence of randomized clinical trials (RCTs) regarding the effect of antiplatelet agents in COVID-19 patients. We originally included data from 5 randomized clinical trials, but only 4 provided available data to meet our quantitative evaluation, all of which were judged to be at low risk to some concern of bias. Only nine percent of participants completed the ACTIV-4B trial of aspirin in clinically stable outpatients with COVID-19 symptoms after enrollment because of the fewer adverse outcomes events than expected. The composite endpoint (all-cause death, venous thrombotic event or arterial thrombotic event, or hospitalization for cardiovascular or pulmonary disease) at 45 days was 0.0%, 0.7%, 1.4%, and 0.0%, respectively. The low occurrence, probably caused by the generally exhibited relatively mild conditions of outpatients, results in its information capacity being too low to conduct analysis.


This systematic review and meta-analysis examined data gathered from 5 recently published RCTs. The outcome revealed that while the use of antiplatelet agents exhibited no significant benefit on all-cause death, the upper bound of the confidence interval on all-cause death (CI 0.83–1.05) suggested that it was unlikely to be a substantiated harm risk associated with this treatment. Moreover, a slight benefit of all-cause death and survival to hospital discharge was observed in critically ill patients but not in non-critically ill cases, which needs further confirmation. However, evidence from all RCTs suggested a high risk of major bleeding in antiplatelet agent treatments. According to the results of our sequential analysis, the evidence available to support or negate the use of antiplatelet agents in COVID-19 patients is lacking. The results of ongoing and future well-designed, large, randomized clinical trials are needed.

Citation: Duo H, Jin M, Yang Y, Baheti R, Feng Y, Fu Z, et al. (2024) Effect of antiplatelet therapy after COVID-19 diagnosis: A systematic review with meta-analysis and trial sequential analysis. PLoS ONE 19(2): e0297628.

Editor: Mohamed Saad, Hamad Medical Corporation, QATAR

Received: March 25, 2023; Accepted: January 9, 2024; Published: February 1, 2024

Copyright: © 2024 Duo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its supporting information files.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.



The Healthcare Patient Experience & Engagement Summit 2024Healthcare Innovation & Transformation SummitHealthcare CNO SummitHealthcare CMO Summit