A study on the effect of aspirin on clinical symptoms, laboratory indices, and outcomes in patients with COVID-19

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Azizi R et al Current data suggest that a high percentage of severe COVID-19 patients have coronary artery disease (CAD), since CAD may be associated with an elevated risk of COVID-19-related mortality in hospitalized patients (2).
According to a previous study, aspirin consumption is associated with decreased mechanical ventilation, intensive care unit (ICU) admission, in-hospital mortality, and decreased clinical symptoms in COVID-19 patients admitted to the hospital.COVID-19 infection manifests in patients with acute conditions associated with elevated coagulation risks (3).Few studies have been conducted to examine the relationship between aspirin administration and the risk of reduced mechanical ventilation, ICU admission, clinical symptoms, and hospital mortality.
Previous experiments suggest that the adimistration of aspirin is associated with improvements in the conditions of hospitalized COVID-19 patients.Low-dose aspirin is one of the most commonly used agents for secondary prevention of cardiovascular disease, and it has been demonstrated that it effectively reduces the risk of heart attack and stroke (4)(5)(6).
Viral infections are an unstable risk factor for chronic cardiovascular disease and a reduction in the heart's intrinsic reserve due to chronic cardiovascular disease and increased metabolic demands resulting from viral infection.Viral infections also induce systemic inflammatory responses and coronary plaque instability.Meanwhile, the new SARS-CoV-2 may increase the risk of acute cardiovascular events, according to the available evidence.Moreover, pneumonia may affect the cardiovascular system either directly or indirectly.In addition, thrombocytopenia causes lung and capillary tissue damage in 5 to 41% of patients with COVID-19 due to decreased bone marrow production and increasing DIC (disseminated intravascular coagulation) (3)(4)(5).Aspirin reduces the production of interleukin-6 and macrophage colony-stimulating factors in COVID-19 patients with cardiovascular disease.Moreover, aspirin irreversibly inhibits platelet cyclooxygenase (COX), and its effect can persist for the circulating platelets' lifespan (7,8).
In contrast to individuals without diabetes, COVID-19 infection in diabetics is associated with an increased risk of severe diseases, pneumonia, hospitalization in the ICU, the need for ventilation, and death.However, it is unclear how much of this increased risk could be attributed to high blood glucose because individuals with diabetes (particularly type 2) have other risk factors for severe COVID-19 (such as older age, obesity, and cardiovascular disease) compared to those without diabetes (9).

Objectives
This study aims to examine the effect of aspirin consumption on the severity of clinical symptoms, laboratory indices, deaths, and recovery in four categories as the following groups; (1) COVID-19 patients with diabetes, (2) COVID-19 patients with cardiovascular disease and diabetes, (3) COVID-19 patients with cardiovascular disease, (4) COVID-19 infected patients without underlying medical conditions, they were divided into aspirin users and non-users.

Study design
This study examined 5000 files of COVID-19 patients hospitalized at the Dr. Shariati hospital in Isfahan between January 1, 2021, and May 10, 2021.The patients were divided into two groups: those administered 80 mg of aspirin (population A) and those without (population B).
Case group selection from population A and control group selection from population B were initially made by non-random selection (at this stage, only documents of COVID-19-infected patients accompanied by patients who had an underlying cardiovascular disease, diabetes, cardiovascular with diabetes, and no underlying diseases were divided, and the population of two groups of A and B were subsequently designated.At this stage, a sample of 170 documents was selected randomly from the case group.Then, after examining the documents, 39 files were deleted due to errors in the clinical or laboratory data, and 131 documents representing the population of cases were added to the study.Following matching (according to age-gender and underlying disease), the control group (131 documents) was included in the study alongside the case group.
This study was observational and cross-sectional; information on both groups was gathered from documents and questionnaires.After selecting the case group and the control group (matching in terms of age, gender, and underlying disease) based on the available data in the files, information was recorded equitably based on the variables table, and their significance was analyzed.
Records for individuals under 40 years old were excluded from the study group, and each document in the study group was divided into two age groups; 40 to 60 years and over 60 (aspirin consumption is typically prescribed for individuals over 40 years).Consequently, by analyzing the characteristics above, we were able to compare the two individual groups (each comprising 131 records).
The indices recorded by nurses and physicians at the files on the first day of admission to the hospital emergency department were noted and compared to examine the effect of aspirin use on the clinical and laboratory indices for study groups (Figure 1).
This study evaluates the effect of aspirin throughout clinical symptoms and laboratory indices in patients with COVID-19.Finally, this research will provide physicians, nurses, and hospital staff, as well as the entire community, with a general understanding of this disease.
The study indices were divided into two categories; matched indices and examined indices.

Statistical analysis
The data were organized in frequency tables, and the results were presented as percentages.The chi-square test and the P value were utilized to compare percentages.Statistical analysis was performed using SPSS (version 18, Chicago, IL, USA).A P < 0.05 was considered statistically significant.

Results
This study examined 131 patients assigned to the aspirin group and 131 patients assigned to the control group.Age and gender were matched between two groups of patients; 22 in the aspirin group and 23 in the control group, aged 40 to 60 years (P = 0.826).Regarding gender, 77 individuals were present in both groups (P = 0.884).In the two groups of patients, both cardiovascular disease and diabetes histories were prevalent (P = 0.959).There was no significant difference in blood oxygen saturation (O 2 Sat) between the two groups (P = 0.240).There was no significant difference between the two groups in terms of prescription drugs, including warfarin, remdesivir, corticosteroids, and antibiotics, however interferon prescriptions were higher in the aspirin group (P = 0.005; Table 1).
The most prevalent symptoms in both groups were dyspnea (P = 0.210) and cough (P = 0.266), whereas body aches (P = 0.001), nausea (P = 0.094), and sore throat (P = 0.001) were more prevalent in the control group, and fever (P = 0.172) was more prevalent in the aspirin group (Figure 2).
The results of laboratory variables between the aspirin and control groups indicate that, in almost all instances, there was no statistically significant difference between the two groups, except for the WBC mean, which was significantly higher in the aspirin group than in the control group (P = 0.009; Table 2).
The examination of the difference between treatment needs and outcomes of COVID-19 patients in the two groups of aspirin and intervention revealed no statistically significant difference (P = 0.962) between the two groups regarding the need for BiPAP and ventilator (P = 0.0111 and P = 0.089, respectively) during the treatment process Azizi R et al  and outcome occurrence, including improvement and death.There was no significant difference in hospitalization duration between the aspirin and control groups (P = 0.289; Table 3).

Discussion
In most cases, coronavirus 2019 (COVID-19) is mild, but fatality has been reported in 6% to 19% of cases.Although pneumonia and acute respiratory distress syndrome (ARDS) are the most common symptoms, thrombotic complications have been reported in 25%-42% of patients and are associated with increased mortality risk.
Coagulation tests have revealed hypercoagulopathy, and D-dimer and fibrinogen concentrations are frequently elevated in COVID-19 patients.Moreover, alveolar capillary micro thrombosis, arterial thrombosis, and platelet thrombosis are observed in the heart, lung, and kidney of COVID-19 patients (3).
According to one study, aspirin may have lung protective effects, reducing the need for mechanical ventilation, ICU hospitalization, and in-hospital mortality in COVID-19 patients.According to studies, there has not been a significant increase in major bleeding in aspirin patients.This disparity may be explained by the fact that COVID-19 patients are excessively hypercoagulable.Thrombocytopenia is uncommon in COVID-19 patients, and the risk of bleeding appears low even when heparin is used (4).
A previous study demonstrated that systemic anticoagulants decrease mortality in COVID-19 patients receiving mechanical ventilation.Low-dose aspirin has been used to prevent brain and heart stroke in highrisk patients, and the US Preventive Services Task Force mandated its use for adults at risk of heart attack (6).
The anti-inflammatory properties of Aspirin may contribute to COVID-19 disease's pulmonary protective effects.It has been demonstrated that aspirin reduces the production of interleukin-6, C-reactive protein, and  macrophage colony-stimulating factors in COVID-19positive cardiovascular disease patients.ARDS has been the subject of multiple studies examining the potential benefits of aspirin.Overall, aspirin may reduce the incidence of ARDS (7).

Conclusion
Aspirin is ineffective throughout clinical symptoms, laboratory indices, and outcomes in patients with COVID-19.

Limitations of the study
• 1-It is evident that recorded information in studies is retrospective, and if the study was based on an interview, the most significant bias is the reminder bias.In order to reduce this bias during the study, the examination of this indicator, the history of aspirin use in patients who still consume aspirin (case group) however have no history of consumption (control group) was considered for inclusion in the study (while the reminder bias of cigarette and warfarin use could influence the outcome).• Selection bias occurs in some studies based on hospital information (using archived files) because the information was not completely and equally recorded in hospital files (documents) and was not recorded for specific research use.Furthermore, the study's eligible population may not represent the reference population.• The documents were chosen randomly from all files to lessen this type of bias.Since only one hospital was examined in this study, selection bias may have influenced the results.

Figure 1 .
Figure 1.Diagram of study design.

Figure 2 .
Figure 2. Frequency distribution of patients' symptoms in two aspirin and control groups among COVID-19 infected patients.

Table 1 .
Frequency distribution of demographic variables, contextual factors, and prescription drugs in COVID-19-infected patients treated with aspirin and control group

Table 2 .
Mean values of laboratory variables between aspirin and control groups

Table 3 .
Examination of the difference between treatment needs and outcomes of infected COVID-19 patients between two groups of aspirin and intervention