Aspirin and P2Y12 inhibitors in treating COVID-19.

Dear Editor, Despite the introduction of vaccines, the coronavirus disease of 2019 (COVID-19) is still a major concern due to uncertainty in efficient treatment and managing post-infection complications. Many randomized controlled trials (RCTs) have been conducted to investigate the effects of non-direct anti-viral medications on COVID-19 patients. A group of these trials has investigated the effect of antiplatelets, including aspirin and/or P2Y12 inhibitors (P2Y12i), including three recently published trials in the past two months: ACTCOVID19 (Anti-Coronavirus Therapies to Prevent Progression of COVID-19) [[1]Eikelboom J.W. et al.Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial.Lancet Respir Med. 2022; Google Scholar], COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-Ill COVID-19 Patients) [[2]Bohula E.A. et al.Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients with COVID-19: COVID-PACT.Circulation. 2022; Crossref Scopus (23) Google Scholar], and RESIST (Statin and Aspirin in SARS-CoV-2 infection) [[3]Ghati N. et al.Statin and aspirin as adjuvant therapy in hospitalised patients with SARS-CoV-2 infection: a randomised clinical trial (RESIST trial).BMC Infect Dis. 2022; 22: 606Crossref PubMed Scopus (15) Google Scholar]. We present here the results of a meta-analysis conducted to evaluate the efficacy and safety of antiplatelets in COVID-19 treatment. Two reviewers (AK and AHB) searched PubMed, SCOPUS, Web of Science, Embase, and Cochrane Library through October 2022 for trials comparing outcomes in COVID-19 patients receiving antiplatelets (aspirin and P2Y12i) and control. Relevant keywords to COVID-19 and antiplatelets (e.g., aspirin, clopidogrel, or ticagrelor) were used in the search. Study characteristics of each study, including location, registration code, design, population, trial arms, and follow-up days, were extracted. We defined primary outcome as all-cause mortality (ACM). Secondary outcomes were in-hospital mortality, need for mechanical ventilation, thrombotic events, major thrombotic events (MTE), major bleeding (MB), and venous thromboembolism (VTE). MTE ໿included pulmonary embolism, acute limb ischemia, stroke, and myocardial infarction, while thrombotic events comprised MTE plus VTE. Meta-analyses were performed by Random-effect analysis by Der-Simonian and Laird method using STATA software (Stata/MP 17.0; StataCorp LLC, College Station, TX, USA). Risk ratios (RRs) with a 95% confidence interval (CI) were reported. The initial search resulted in 1,244 records, of which 557 were duplicates, 634 were removed after screening with title and abstract, and 46 were excluded after full-text assessment due to being observational, lack of control group, or not including antiplatelets. Finally, seven RCTs consisting of 21,942 COVID-19 patients were included in our analyses. Table 1 summarizes the study characteristics of included RCTs.Table 1Study characteristics of randomized controlled trials.Trial NameACTCOVID19 2022ACTIV-4A 2022ACTIV-4B 2022RECOVERY 2021REMAP-CAP 2022RESIST 2022COVID-PACT 2022DesignOpen labelOpen labelDouble blindOpen labelOpen labelOpen labelOpen labelRegistrationNCT04324463NCT04505774NCT04498273NCT04381936NCT02735707CTRI/2020/07/026791NCT04409834Location (s)11 countriesBrazil, Italy, Spain and the United StatesUnited StatesUnited Kingdom, Indonesia, and Nepal8 countriesIndiaUnited StatesPopulationAdults aged >30 with symptomatic laboratory-confirmed COVID-19 not requiring hospitalizationPatients with laboratory-confirmed SARS-CoV-2 infection who were hospitalized for COVID-19Ambulatory patients aged 40 to 80 with newly diagnosed symptomatic SARS-CoV-2 infection with positive PCR or antigen test resultsAdults clinically suspected or microbiologically confirmed COVID-19 who were admitted to hospitalAdults clinically suspected or microbiologically confirmed CVID-19 who were admitted to hospitalPCR-positive COVID-19 patients aged 40 to 75 who were hospitalized due to symptomsAdults with acute SARS-CoV-2 infection who required ICU admissionAntiplatelet arm (s)Aspirin (100 mg daily)P2Y12i (different dosage based on the drug used) + heparin*Heparin was administered at its therapeutic dose. COVID-19: coronavirus disease of 2019, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2, PCR: polymerase chain reaction, ICU: intensive care unit, P2Y12i: P2Y12 inhibitors, WHO: world health organization.Aspirin (81 mg daily)Aspirin (150 mg daily)Group 1) Aspirin (75 to 100 mg daily)Group 2) P2Y12i (clopidogrel 75 mg daily; ticagrelor 60 mg loading dose followed by 5 or 10 mg daily)Aspirin (75 mg daily)P2Y12i: Clopidogrel (300 mg loading dose followed by 75 mg daily)Antiplatelet duration (days)2814 or until discharge45Until discharge14 or until discharge10 or until dischargeMedian= 8.6Control armUsual careUsual care + heparin*Heparin was administered at its therapeutic dose. COVID-19: coronavirus disease of 2019, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2, PCR: polymerase chain reaction, ICU: intensive care unit, P2Y12i: P2Y12 inhibitors, WHO: world health organization.PlaceboUsual careUsual careUsual careUsual careFollow-up (days)45907528 or until discharge9010 or until discharge28 or until dischargePrimary outcome of the trialA composite of major thrombosis, hospitalization, or deathMajor bleeding and composite of organ support-free days, in-hospital death, alive and free of organ support, and alive with organ supportA composite of thrombotic events, or hospitalization for cardiovascular or pulmonary cause28-day mortalityOrgan support–free daysClinical deterioration to WHO Ordinal Scale for Clinical Improvement ≥6A composite of thrombotic events Heparin was administered at its therapeutic dose.COVID-19: coronavirus disease of 2019, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2, PCR: polymerase chain reaction, ICU: intensive care unit, P2Y12i: P2Y12 inhibitors, WHO: world health organization. Open table in a new tab Fig. 1 presents the meta-analysis results of antiplatelets compared to usual care. Pooled meta-analysis resulted in no significant difference in terms of ACM (RR 0.93, 95% CI: 0.83-1.04, P=0.19), in-hospital mortality (RR: 0.84, 95% CI: 0.64-1.10, P=0.21), need for mechanical ventilation (RR: 0.95, 95% CI: 0.87-1.04, P=0.29), thrombotic events (RR: 0.89, 95% CI: 0.70-1.13, P=0.32), MTE (RR: 0.99, 95% CI: 0.48-2.06, P=0.98), or VTE (RR: 0.78, 95% CI: 0.59-1.03, P=0.08). However, MB was significantly higher among patients receiving antiplatelet agents (RR: 2.84, 95% CI: 1.11-7.30, P=0.03). The suggestion of antiplatelet agents was based on higher VTE and disseminated intravascular coagulation rates in COVID-19 patients reported in some studies [[4]Bianconi V. et al.Is acetylsalicylic acid a safe and potentially useful choice for adult patients with COVID-19?.Drugs. 2020; 80: 1383-1396Crossref PubMed Scopus (73) Google Scholar]. In addition to their antithrombotic effects, aspirin's anti-inflammatory, antipyretic, and anti-analgesic effects [[5]Diaz T. et al.Aspirin Bioactivity for Prevention of Cardiovascular Injury in COVID-19.Front Cardiovasc Med. 2020; 7562708Crossref PubMed Google Scholar] were other influential factors that contributed to their selection as a therapeutic option in hospitalized patients with COVID-19. However, our study did not find obvious overall benefits in administrating these agents. A recent meta-analysis of observational studies and RCTs by Ma et al. [[6]Ma S. et al.Does aspirin have an effect on risk of death in patients with COVID-19? A meta-analysis.Eur J Clin Pharmacol. 2022; 78: 1403-1420Crossref PubMed Scopus (8) Google Scholar] found a lower mortality rate in patients receiving aspirin compared to healthy controls, which was inconsistent with our result, emphasizing the difference between observational studies and RCTs. This study included the RECOVERY trial as the only RCT [[7]Abani O. et al.Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.The Lancet. 2022; 399: 143-151Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar]. Another study by Zong et al. [[8]Zong X. et al.Antiplatelet therapy for patients with COVID-19: Systematic review and meta-analysis of observational studies and randomized controlled trials.Front Med (Lausanne). 2022; 9965790Google Scholar] included three RCTs in the systematic review; however, none were included in meta-analyses. In our study, subgroup analyses based on the antiplatelet agent (aspirin or P2Y12i) resulted in nonsignificant differences for all outcomes in patients receiving aspirin compared to controls (Supplementary figures 1-2). However, MB was significantly higher (RR: 2.84, 95% CI: 1.06-7.62, P=0.04) and VTE was also significantly lower (RR: 0.70, 95% CI: 0.50-0.99, P=0.04) in patients receiving P2Y12i (Supplementary figure 1). As the apparent efficacy of these agents in cohort studies could not be confirmed with RCTs, there may be a reduced need for focusing on these medications in clinical practice and future research. Although this study demonstrated no beneficiary effect for antiplatelet drugs in COVID-19 patients, some limitations should be addressed. First, as the primary outcome, ACM was the most reported outcome in the studies, which does not differentiate the cause of death, such as cardiovascular, thromboembolic, or other reasons. Second, the limited number of trials for some outcomes could affect their generalizability, even when the overall pooled results were insignificant. Third, there was no subgroup analysis for age, gender, or other comorbidities; hence, we could not determine any result for these populations. Finally, the different dosages of aspirin and the difference in P2Y12i agents could have impacted our results. To the best of our knowledge, this is the most comprehensive meta-analysis, consisting of seven RCTs to compare the antiplatelet medications with controls in COVID-19 patients. In conclusion, in treating COVID-19 patients, our study did not find significant benefit from adding antiplatelets in terms of mortality and other efficacy outcomes, while using P2Y12i was associated with a higher risk of MB. AK and AHB: Study conception, design, analysis, and writing; SP: Study conception, writing, and critical revision. The authors declare they have no conflict of interest. None.