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. 2023 Jul 25;7(7):CD015078.
doi: 10.1002/14651858.CD015078.

Antiplatelet agents for the treatment of adults with COVID-19

Anna-Lena Fischer #  1 , Sarah Messer #  2 , Rachel Riera  3   4   5 , Ana Luiza C Martimbianco  3   4   6 , Miriam Stegemann  7 , Lise J Estcourt  8 , Stephanie Weibel  9 , Ina Monsef  2 , Marike Andreas  2 , Rafael L Pacheco #  4   5   10 , Nicole Skoetz #  2
Affiliations

Antiplatelet agents for the treatment of adults with COVID-19

Anna-Lena Fischer et al. Cochrane Database Syst Rev. .

Abstract

Background: Severe coronavirus disease 2019 (COVID-19) can cause thrombotic events that lead to severe complications or death. Antiplatelet agents, such as acetylsalicylic acid, have been shown to effectively reduce thrombotic events in other diseases: they could influence the course of COVID-19 in general.

Objectives: To assess the efficacy and safety of antiplatelets given with standard care compared to no treatment or standard care (with/without placebo) for adults with COVID-19.

Search methods: We searched the Cochrane COVID-19 Study Register (which comprises MEDLINE (PubMed), Embase, ClinicalTrials.gov, WHO ICTRP, medRxiv, CENTRAL), Web of Science, WHO COVID-19 Global literature on coronavirus disease and the Epistemonikos COVID-19 L*OVE Platform to identify completed and ongoing studies without language restrictions to December 2022.

Selection criteria: We followed standard Cochrane methodology. We included randomised controlled trials (RCTs) evaluating antiplatelet agents for the treatment of COVID-19 in adults with COVID-19, irrespective of disease severity, gender or ethnicity.

Data collection and analysis: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane risk of bias tool (RoB 2) for RCTs. We rated the certainty of evidence using the GRADE approach for the outcomes.

Main results: Antiplatelets plus standard care versus standard care (with/without placebo) Adults with a confirmed diagnosis of moderate to severe COVID-19 We included four studies (17,541 participants) that recruited hospitalised people with a confirmed diagnosis of moderate to severe COVID-19. A total of 8964 participants were analysed in the antiplatelet arm (either with cyclooxygenase inhibitors or P2Y12 inhibitors) and 8577 participants in the control arm. Most people were older than 50 years and had comorbidities such as hypertension, lung disease or diabetes. The studies were conducted in high- to lower middle-income countries prior to wide-scale vaccination programmes. Antiplatelets compared to standard care: - probably result in little to no difference in 28-day mortality (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.85 to 1.05; 3 studies, 17,249 participants; moderate-certainty evidence). In absolute terms, this means that for every 177 deaths per 1000 people not receiving antiplatelets, there were 168 deaths per 1000 people who did receive the intervention (95% CI 151 to 186 per 1000 people); - probably result in little to no difference in worsening (new need for invasive mechanical ventilation or death up to day 28) (RR 0.95, 95% CI 0.90 to 1.01; 2 studies, 15,266 participants; moderate-certainty evidence); - probably result in little to no difference in improvement (participants discharged alive up to day 28) (RR 1.00, 95% CI 0.96 to 1.04; 2 studies, 15,454 participants; moderate-certainty evidence); - probably result in a slight reduction of thrombotic events at longest follow-up (RR 0.90, 95% CI 0.80 to 1.02; 4 studies, 17,518 participants; moderate-certainty evidence); - may result in a slight increase in serious adverse events at longest follow-up (Peto odds ratio (OR) 1.57, 95% CI 0.48 to 5.14; 1 study, 1815 participants; low-certainty evidence), but non-serious adverse events during study treatment were not reported; - probably increase the occurrence of major bleeding events at longest follow-up (Peto OR 1.68, 95% CI 1.29 to 2.19; 4 studies, 17,527 participants; moderate-certainty evidence). Adults with a confirmed diagnosis of asymptomatic SARS-CoV-2 infection or mild COVID-19 We included two RCTs allocating participants, of whom 4209 had confirmed mild COVID-19 and were not hospitalised. A total of 2109 participants were analysed in the antiplatelet arm (treated with acetylsalicylic acid) and 2100 participants in the control arm. No study included people with asymptomatic SARS-CoV-2 infection. Antiplatelets compared to standard care: - may result in little to no difference in all-cause mortality at day 45 (Peto OR 1.00, 95% CI 0.45 to 2.22; 2 studies, 4209 participants; low-certainty evidence); - may slightly decrease the incidence of new thrombotic events up to day 45 (Peto OR 0.37, 95% CI 0.09 to 1.46; 2 studies, 4209 participants; low-certainty evidence); - may make little or no difference to the incidence of serious adverse events up to day 45 (Peto OR 1.00, 95% CI 0.60 to 1.64; 1 study, 3881 participants; low-certainty evidence), but non-serious adverse events were not reported. The evidence is very uncertain about the effect of antiplatelets on the following outcomes (compared to standard care plus placebo): - admission to hospital or death up to day 45 (Peto OR 0.79, 95% CI 0.57 to 1.10; 2 studies, 4209 participants; very low-certainty evidence); - major bleeding events up to longest follow-up (no event occurred in 328 participants; very low-certainty evidence). Quality of life and adverse events during study treatment were not reported.

Authors' conclusions: In people with confirmed or suspected COVID-19 and moderate to severe disease, we found moderate-certainty evidence that antiplatelets probably result in little to no difference in 28-day mortality, clinical worsening or improvement, but probably result in a slight reduction in thrombotic events. They probably increase the occurrence of major bleeding events. Low-certainty evidence suggests that antiplatelets may result in a slight increase in serious adverse events. In people with confirmed COVID-19 and mild symptoms, we found low-certainty evidence that antiplatelets may result in little to no difference in 45-day mortality and serious adverse events, and may slightly reduce thrombotic events. The effects on the combined outcome admission to hospital or death up to day 45 and major bleeding events are very uncertain. Quality of life was not reported. Included studies were conducted in high- to lower middle-income settings using antiplatelets prior to vaccination roll-outs. We identified a lack of evidence concerning quality of life assessments, adverse events and people with asymptomatic infection. The 14 ongoing and three completed, unpublished RCTs that we identified in trial registries address similar settings and research questions as in the current body of evidence. We expect to incorporate the findings of these studies in future versions of this review.

Trial registration: ClinicalTrials.gov NCT04505774 NCT04409834 NCT04498273 NCT04324463 NCT04381936 NCT02735707 NCT04391179 NCT04363840 NCT04365309 NCT04445623 NCT04703608 NCT04768179 NCT04808895 NCT04937088 NCT05073718.

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Conflict of interest statement

AF: works as an Intensive Care Medicine Physician and is member of the CEOsys project funded by the Network of University Medicine (Nationales Forschungsnetzwerk der Universitätsmedizin (NUM)) by the Federal Ministry of Education and Research of Germany (Bundesministerium für Bildung und Forschung (BMBF)), grant number 01KX2021, paid to the institution.

SM: none known; she is a staff member of Cochrane Haematology, but was not involved in the editorial process for this review.

RR: none known.

AM: none known.

MS: none known.

LE: she is Co‐ordinating Editor of Cochrane Haematology, but was not involved in the editorial process for this review. She is an investigator on the REMAP‐CAP trial but was not involved in the data extraction or risk of bias assessment of this trial.

SW: none known; she is Content Editor of Cochrane Anaesthesia, but was not involved in the editorial process for this review.

IM: none known; she is an Information Specialist of Cochrane Haematology, but was not involved in the editorial process for this review.

MA: none known.

RP: none known.

NS: none known; she is Co‐ordinating Editor of Cochrane Haematology, but was not involved in the editorial process for this review.

Figures

1
1
Study flow diagram
1.1
1.1. Analysis
Comparison 1: Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease, Outcome 1: All‐cause mortality up to day 28
1.2
1.2. Analysis
Comparison 1: Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease, Outcome 2: Worsening up to day 28: participants with new need for invasive mechanical ventilation or death
1.3
1.3. Analysis
Comparison 1: Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease, Outcome 3: Improvement up to day 28: discharged alive
1.4
1.4. Analysis
Comparison 1: Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease, Outcome 4: Thrombotic events
1.5
1.5. Analysis
Comparison 1: Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease, Outcome 5: Serious adverse events
1.6
1.6. Analysis
Comparison 1: Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease, Outcome 6: Major bleeding events
1.7
1.7. Analysis
Comparison 1: Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease, Outcome 7: Need for new dialysis up to day 28
1.8
1.8. Analysis
Comparison 1: Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease, Outcome 8: 180‐day mortality
1.9
1.9. Analysis
Comparison 1: Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease, Outcome 9: All‐cause mortality up to longest follow‐up
2.1
2.1. Analysis
Comparison 2: Subgroup analysis: Effects on mortality up to day 28, Outcome 1: Subgroup analysis (type of antiplatelet agent): cyclooxygenase inhibitors or ADP receptor/P2Y12 inhibitors in participants with moderate to severe COVID‐19
2.2
2.2. Analysis
Comparison 2: Subgroup analysis: Effects on mortality up to day 28, Outcome 2: Subgroup analysis: concomitant therapeutic dose anticoagulation or prophylactic anticoagulation
3.1
3.1. Analysis
Comparison 3: Individuals with a confirmed diagnosis of SARS‐CoV‐2 infection and asymptomatic to mild disease, Outcome 1: All‐cause mortality up to longest follow‐up (45 days)
3.2
3.2. Analysis
Comparison 3: Individuals with a confirmed diagnosis of SARS‐CoV‐2 infection and asymptomatic to mild disease, Outcome 2: Admission to hospital or death up to day 45
3.3
3.3. Analysis
Comparison 3: Individuals with a confirmed diagnosis of SARS‐CoV‐2 infection and asymptomatic to mild disease, Outcome 3: Thrombotic events
3.4
3.4. Analysis
Comparison 3: Individuals with a confirmed diagnosis of SARS‐CoV‐2 infection and asymptomatic to mild disease, Outcome 4: Serious adverse events
See this image and copyright information in PMC

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