Antiplatelet therapy for patients with COVID-19: Systematic review and meta-analysis of observational studies and randomized controlled trials

Abstract

BackgroundHyperinflammation and coagulopathy are hallmarks of COVID-19 and synergistically contribute to illness progression. Antiplatelet agents have been proposed as candidate drugs for COVID-19 treatment on the basis of their antithrombotic and anti-inflammatory properties. A systematic review and meta-analysis that included early observational studies and recent randomized controlled trials (RCTs) was performed to summarize and compare evidence on this issue.MethodsPubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched to identify studies published up to Nov 7, 2021, and the results of registered clinical trials were followed up to Mar 30, 2022. We included RCTs and observational studies assessing the effect of antiplatelet therapy in adult patients with COVID-19. Data on baseline patient characteristics, interventions, controls, and outcomes were extracted by two independent reviewers. The primary outcome was mortality. Data were pooled using a random-effects model.ResultsTwenty-seven studies were included, of which 23 observational studies were pooled in a meta-analysis, and the remaining four RCTs (ACTIV-4B, RECOVERY, ACTIV-4a, and REMAP-CAP) were narratively synthesized. Based on 23 observational studies of 87,824 COVID-19 patients, antiplatelet treatment favors a lower risk of mortality [odds ratio (OR) 0.72, 95% confidence interval (CI) 0.61–0.85; I2 = 87.0%, P < 0.01]. The narrative synthesis of RCTs showed conflicting evidence, which did not support adding antiplatelet therapy to the standard care, regardless of the baseline illness severity and concomitant anticoagulation intensity.ConclusionWhile the rationale for using antiplatelet treatment in COVID-19 patients is compelling and was supported by the combined result of early observational studies, evidence from RCTs did not confirm this approach. Several factors that could explain this inconsistency were highlighted alongside perspectives on future research directions.

Effects of the circulating environment of COVID-19 on platelet and neutrophil behavior

“…COVID-19 is associated with prothrombotic proinflammatory biologic profiles thought to mediate the thromboinflammatory clinical complications. Although evidence has accumulated that platelets and neutrophils are both crucial cellular contributors to the thromboinflammation of COVID-19 ( 25 ), therapeutic targeting of these cellular contributors to improve morbidity and mortality of COVID-19 has proven difficult ( 26 ). Further, the effect of the circulating soluble environment on this platelet-neutrophil axis has not been fully elucidated.…”

Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19

“…Furthermore, under the prothrombotic environment in severe COVID-19 77,82,83 , aberrantly glycosylated anti-spike immune complexes can trigger platelet activation leading to thrombus formation. Ample evidence now supports the beneficial role of anti-platelet medication in COVID-19 treatments 84,85 . Therefore, as the altered glycosylation pattern of Fc tail on IgGs is transient in the early phase of seroconversion, the selective effect of entospletinib in counterbalancing thrombus formation against aberrantly glycosylated immune complex could be beneficial to prevent severe COVID-19.…”

Platelets in COVID-19 disease: friend, foe, or both?

“…In the P2Y 12 inhibitor group, ticagrelor was used in 63% of patients and clopidogrel in 37% Among non-critically ill patients hospitalized for COVID-19, the use of a P2Y 12 antagonist in addition to a therapeutic dose of heparin, compared with a therapeutic dose of heparin only, did not result in increased odds of improvement in organ support-free days within 21 days during hospitalization [ 84 ] 2 COVID-19 outpatient thrombosis prevention trial A Multi-center adaptive randomized placebo-controlled platform trial evaluating the efficacy and safety of anti-thrombotic strategies in COVID adults not requiring hospitalization at time of diagnosis (ACTIV-4B trial), ( n = 657) Apixaban 2.5 mg, Apixaban 5 mg, Aspirin (low-dose 81 mg), Placebo Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with a placebo did not reduce the rate of a composite clinical outcome [ 85 ] 3 RECOVERY trial ( n = 14,892) Adult COVID-19 patients were randomly allocated in a 1:1 ratio to either the usual standard of care plus 150 mg aspirin once per day until discharge or the usual standard of care alone. The primary outcome was 28-day mortality A similar number of COVID-19 patients with aspirin in addition to the usual standard of care group and the usual standard care group died within 28 days [ 87 ] 4 REMAP-CAP trial ( n = 1549) Treatment with an antiplatelet agent: aspirin or a P2Y 12 inhibitor (clopidogrel, prasugrel, or ticagrelor) compared with no antiplatelet agent Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support—free days within 21 days [ 86 ] 5 Observational studies Pooled 23 observational studies in a meta-analysis [ 88 ] Antiplatelet treatment favored a lower risk of mortality [odds ratio (OR) 0.72, 95% confidence interval (CI) 0.61–0.85; I 2 = 87.0%, P < 0.01] Evidence from large randomized clinical trials listed as 1–4 did not confirm the therapeutic efficacy of antiplatelet drugs in severe COVID-19, while the rationale for using antiplatelet treatment in COVID-19 was initially supported by the result of the early observational studies (based on [ 88 ]) …”

“… Evidence from large randomized clinical trials listed as 1–4 did not confirm the therapeutic efficacy of antiplatelet drugs in severe COVID-19, while the rationale for using antiplatelet treatment in COVID-19 was initially supported by the result of the early observational studies (based on [ 88 ]) …”