key: cord-0750476-ci2p8bv0
authors: Martha, Januar Wibawa; Pranata, Raymond; Lim, Michael Anthonius; Wibowo, Arief; Akbar, Mohammad Rizki
title: Active Prescription of Low-dose Aspirin During or Prior to Hospitalization and Mortality in COVID-19 — A Systematic Review and Meta-analysis of Adjusted Effect Estimates
date: 2021-05-15
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.05.016
sha: 57172913e86ffb3a0713282b4a8932844456e794
doc_id: 750476
cord_uid: ci2p8bv0

BACKGROUND: This study aims to investigate whether the active prescription of low-dose aspirin during or prior to hospitalization affects mortality in COVID-19 patients. Aspirin is often prescribed for secondary prevention in patients with cardiovascular disease and other comorbidities that might increase mortality, thus, may falsely demonstrate increased mortality. To reduce bias, we only enrolled studies that performed the adjusted analysis. METHODS: A systematic literature search was performed using PubMed, Scopus, Embase, and Clinicaltrials.gov from the inception of the database up until 16 April 2021. The exposure was active prescription of low-dose aspirin during or prior to hospitalization. The primary outcome was mortality. The pooled adjusted effect estimate was reported as relative risk (RR). RESULTS: There were 6 eligible studies that were included in this meta-analysis, comprising of 13,993 patients. The studies have a low-moderate risk of bias based on Newcastle-Ottawa Scale. Meta-analysis indicates that low-dose aspirin use was independently associated with reduced mortality (RR 0.46 [0.35, 0.61], p < 0.001; I(2): 36.2%). Subgroup analysis on in-hospital low-dose aspirin administration also showed statistically significant mortality reduction (RR 0.39 [0.16, 0.96], p < 0.001; I(2): 47.0%). CONCLUSION: Low-dose aspirin use is independently associated with reduced mortality in patients with COVID-19 with a low certainty of evidence. PROSPERO: CRD42021249440.

(COX) activity. Low-dose aspirin inhibits COX-1, resulting in reduced thromboxane A2 synthesis. (Bianconi et al., 2020; Mohamed-Hussein et al., 2020) This study aims to investigate whether the active prescription of low-dose aspirin during or prior to hospitalization affects mortality in COVID-19 patients. Aspirin is often prescribed for secondary prevention in patients with cardiovascular disease and other comorbidities that might be associated with increased mortality in patients with COVID-19 Yonas et al., 2020) , thus, may falsely demonstrate increased mortality. To reduce such bias, we only enrolled studies that performed the adjusted analysis with or without the use of propensity score matching. We also enrolled only patients that have an active prescription by excluding studies with unclear information on whether aspirin use was historical or current, to ensure that aspirin is active in the system during COVID-19 infection.

This is a Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) compliant systematic review and meta-analysis; and is registered in PROSPERO (CRD42021249440).

A systematic literature search was performed using PubMed, Scopus, Embase, and Clinicaltrials.gov using the keywords "(Coronavirus Disease 2019 OR COVID-19 OR SARS-CoV-2 OR 2019-nCoV) AND (aspirin OR acetylsalicylic acid OR acetylsalicylate)" from the inception of databases up until 16 April 2021. The title/abstracts of the articles were screened and assessed for eligibility based on the inclusion and exclusion criteria. Discrepancies were resolved by discussion.

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The exposure was low-dose aspirin use, defined as active prescription of low-dose aspirin (75 to 325 mg daily) during or prior to hospitalization (maximum of 7 days). We exclude studies with unclear information on whether aspirin use was historical or current. The control group was no active prescription of low-dose aspirin during or prior to hospitalization. The primary outcome was mortality.

We included studies that met the following criteria: 1) observational studies or randomized controlled trials evaluating patients hospitalized for COVID-19, 2) low-dose aspirin use versus control group, and 3) adjusted effect estimate for mortality.

We exclude studies that met at least one of the following criteria: 1) abstract-only publication, 2) non-research letters, 3) reviews, and 4) commentaries or editorial. No language restriction was imposed.

Two authors independently performed data extraction from the included studies. The data of interests were the first author, study design, sample size, percentage of severe COVID-19, inclusion criteria, age, male sex, hypertension, diabetes, coronary artery disease, adjusted effect estimates for mortality, and adjustment factors. Discrepancies were resolved by discussion.

To assess the risk of bias, two independent authors used the Newcastle Ottawa Scale (NOS) for cohort studies. (Wells et al., 2000) NOS comprise of three domains: 1) selection, 2) comparability, J o u r n a l P r e -p r o o f and 3) outcome of the included studies. Discrepancies were resolved by discussion. To determine the certainty of evidence, we used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.

The primary outcome was mortality, defined as clinically validated death. We pooled the adjusted effect estimates of the included studies. The pooled effect estimate was reported as relative risk (RR), defined as adjusted odds ratio, adjusted risk ratio, or adjusted hazard ratio.

We used STATA 16.0 to perform the meta-analysis. The adjusted RRs for low-dose aspirin use and mortality were pooled using Empirical Bayes random-effects model, irrespective of heterogeneity. P-values of ≤ 0.05 for the pooled effect estimates indicate statistical significance.

To evaluate heterogeneity, Cochran's Q test and I 2 statistics were used; I 2 values above 50% or/and p-value below 0.10 indicated substantial heterogeneity. To assess publication bias and small-study effects, we used funnel plot analysis and Egger's test. Non-parametric trim-and-fill analysis was performed due to the asymmetrical funnel plot. Subgroup analysis was performed for studies that clearly indicate in-hospital use of low dose aspirin.

There were ten potentially eligible articles for inclusion. One study was excluded due to unclear confidence interval for adjusted effect estimate, the study showed a significant mortality J o u r n a l P r e -p r o o f reduction with aspirin in univariate analysis. (Karruli et al., 2021) One study did not clearly report whether aspirin use is an active prescription or only a history of exposure, the study reported that there was no significant difference in terms of mortality. (Alamdari et al., 2020) Table 1 . Three studies were propensity score matched cohort (1:1). The inclusion and exclusion criteria of respective studies were displayed in Supplementary Table 1 .

Meta-analysis indicates that low-dose aspirin use was independently associated with reduced mortality (RR 0.46 [0.35, 0.61], p<0.001; I 2 : 36.2%, p=0.155) [ Figure 2 ]. Subgroup analysis on inhospital low-dose aspirin administration also showed statistically significant mortality reduction (RR 0.39 [0.16, 0 .96], p<0.001; I 2 : 47.0%, p=0.170).

Funnel-plot analysis showed slight asymmetry [ Figure 3A ] and after non-parametric trim-and-fill analysis (Linear 0 estimator, right side), the pooled effect estimate remained significant (RR 0.48 J o u r n a l P r e -p r o o f [0.36, 0.65]) [ Figure 3B ]. Egger's test was not statistically significant for small-study effects (p=0.777).

The studies have a low-moderate risk of bias based on NOS. GRADE Assessment showed a low certainty of evidence for the mortality reducing effect of low-dose aspirin, which is mainly due to the retrospective nature of the studies and possibility of selection and publication bias [ Table 2 ].

This meta-analysis indicates that low-dose aspirin use is independently associated with reduced mortality in patients with COVID-19 with a low certainty of evidence.

Aspirin is an antithrombotic agent traditionally prescribed in patients with cardiovascular and cerebrovascular diseases, as well as various non-communicable diseases. Pranata et al., 2020a; Yang et al., 2020) These comorbidities are also associated with higher severity and mortality related to COVID-19, and patients with these chronic, systemic or frail conditions often take aspirin routinely prior to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. (Pranata et al., 2021d (Pranata et al., , 2021c Tuty Kuswardhani et al., 2020) . Thus, patients that routinely uses aspirin may have more comorbidities than those that did not. This may lead to poorer clinical outcome in patients receiving aspirin. To minimize bias, we only enrolled studies that performed the adjusted analysis with or without the use of propensity score matching. There was an apparent benefit of aspirin use after pooling these studies.

Aspirin exerts not only antithrombotic, but also analgesic, anti-pyretic, anti-viral, antiinflammatory, and immunomodulatory actions. Aspirin primarily acts on inhibiting platelet function through irreversible inhibition of cyclooxygenase (COX) activity. In low doses (75-81 mg/day), COX-1 is inhibited and thus thromboxane A2 synthesis by platelet is reduced (antithrombotic), whereas in intermediate-to-high doses (650 to 4000 mg/day), ASA inactivates COX-1 and COX-2, blocks prostaglandin (PG) generation, and produces analgesic, antipyretic, and antiinflammatory effects. (Bianconi et al., 2020; Mohamed-Hussein et al., 2020) Its anti-viral activity is not clearly understood, but seems to limit viral replication by blocking prostaglandin E2 (PGE2) in macrophages and upregulate type I interferon generation. (Mohamed-Hussein et al., 2020) Aspirin also downregulates nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway, cytomegalovirus-induced reactive oxygen species (ROS) formation, inducible nitric oxide synthase (iNOS), oxidative phosphorylation uncoupling, and enhances mitochondria permeability. Aspirin-induced overactivation of heme-oxygenase-1 (HO-1) may lead to heme degradation, which contributes in as a pro-inflammatory mediator, while D,L-lysine acetylsalicylate reduction may result in lower RNA synthesis and replication, as seen in the human CoV-229E and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). (Bianconi et al., 2020) Early antiplatelet therapy may be helpful in the setting of viral pneumonia, given its inhibitory activity on platelet activation and platelet-neutrophil aggregation, which is pivotal in thrombus generation with subsequent lung damage, and increased lipoxin synthesis, which restores the function of pulmonary endothelial cell. Middleton et al., 2016; Xin et al., 2020) In critically ill individuals without COVID-19, aspirin use was associated with a lower J o u r n a l P r e -p r o o f risk of acute respiratory distress syndrome (ARDS) and death. (Du et al., 2018; Wang et al., 2016) .

Thus, the effect may extend beyond COVID-19 specific pathologies. In patients with COVID-19, there are high rates of VTE and disseminated intravascular coagulation (DIC) due to hypercoagulable and hyperaggregability state. (Bianconi et al., 2020; Pavoni et al., 2020) Elevation of inflammatory and coagulation parameters and derangement of various laboratory values are noted in patients with more severe SARS-COV-2 infection, indicating poor prognosis. (Akbar et al., 2021; Huang et al., 2020b) These alteration may lead to cardiac injuries that were strongly associated with mortality. Pranata et al., 2020b; Wibowo et al., 2021a Wibowo et al., , 2021b As cytokine storm is the underlying mechanism behind multisystem inflammatory process in severe COVID-19, the use of aspirin could theoretically a promising option in improving patients' outcomes and hindering the development of fatal complications, including ARDS, coagulopathy, sepsis, multi-organ dysfunction, and death. Pranata et al., 2021e) Aspirin has been found to reduce the generation of C-reactive protein (CRP), interleukin-6 (IL-6), and macrophage colony-stimulating factor, hence helps in mitigating cytokine storm as well as exerting cardio-respiratory protective actions. (Mehta et al., 2020) Moreover, ASA had markedly lower initial plasma fibrinogen level through fibrinogen acetylation and fibrinolysis acceleration, therefore decreasing the risk of thrombotic and bleeding events. However, aspirin belongs to the group of non-steroidal anti-inflammatory drugs (NSAID), whose use is controversial in COVID-19 because it can exacerbate the progression of lung disease. NSAID use can alter neutrophil function and delay bacterial clearance and resolution of J o u r n a l P r e -p r o o f inflammation. (Giollo et al., 2021; Little, 2020; Micallef et al., 2020) Nevertheless, the evidence is vague, and our meta-analysis indicate benefit of aspirin use.

Given its widespread availability, low-cost, and possible efficacy and good safety profile, low dose aspirin should be considered in the treatment of severe and critically ill COVID-19 patients.

However, contraindications and adverse effects of aspirin must always be kept in mind, especially relating to allergy, bleeding risk, and Reye's syndrome in children. Because of low certainty of evidence, the risk and benefit should be weighted before administering aspirin in patients with COVID-19.

This study has several limitations. The included studies were mostly retrospective and thus prone to biases. The cause of mortality in the included studies were not differentiated into thromboembolism, cardiovascular, or all-cause mortality; thus this were unable to provide details with regards to benefit. The prediction of bleeding risk is lacking due to limited data availability. There is a possibility of selection bias because of its observational nature, patients that require aspirin may be at higher risk due to underlying comorbidities or at higher risk of thrombosis; although this is partly mitigated by the multivariable analysis and propensity score matching in several studies. However, in this case, the confounders would reduce the demonstrated effect and may actually increase the benefit. Concomitant angiotensin receptor blocker, anticoagulant, and statin use which were known to decrease mortality may potentially confound the analysis. (Kow and Hasan, 2020; Lemos et al., 2020; Permana et al., 2021; Pranata et al., 2020c; Wijaya et al., 2020) Additionally, even though these analyses were adjusted to J o u r n a l P r e -p r o o f 13 confounders, it does not necessarily mean that all confounders have been adjusted for. There might be confounders that were not reported and analyzed by the authors of the included studies.

Further large double-blinded, placebo controlled RCTs are necessary for a definite conclusion.

Low-dose aspirin use is independently associated with reduced mortality in patients with COVID-19 with a low certainty of evidence. 

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Data are available on reasonable request J o u r n a l P r e -p r o o f