Mortality and pre‐hospitalization use of low‐dose aspirin in COVID‐19 patients with coronary artery disease

Abstract To determine whether pre‐hospitalization use of aspirin is associated with all‐cause mortality in coronavirus disease 2019 (COVID‐19) patients with coronary artery disease (CAD). We recruited 183 adult patients with CAD diagnosed with COVID‐19, including 52 taking low‐dose aspirin (mean [SD] age, 69.7 [1.1] years; 59.6% men) and 131 without using aspirin (mean [SD] age, 71.8 [0.9] years; 51.9% men), who were admitted in the Tongji hospital in Wuhan, China from January 10, 2020 to March 30, 2020. There was no difference on in‐hospital mortality between aspirin group and non‐aspirin group (21.2% vs. 22.1%, P = .885). Similarly, for critically severe COVID‐19 patients, the mortality in aspirin group was close to that in non‐aspirin group (44% vs. 45.9%, P = .872). Moreover, the percentage of patients with CAD taking low‐dose aspirin did not differ between those survivors and non‐survivors (28.7% vs. 27.5%, P = .885). Meanwhile, the usage of aspirin was not correlated with all‐cause mortality in multivariate analysis (OR = 0.944, 95% CI: 0.411‐2.172, P = .893). Collectively, our study suggested that the pre‐hospitalization use of low‐dose aspirin was not associated with the clinical outcome of patients with CAD hospitalized with COVID‐19 infections.


| INTRODUC TI ON
In December 2019, the coronavirus disease 2019 , caused by an infection with a novel coronavirus, officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in Wuhan, Hubei province, China. 1 Emerging data suggest that patients with severe COVID-19 have a relative high incidence of coronary artery disease (CAD) and CAD may be associated with an high risk of mortality due to COVID-19 among patients admitted to hospital. [2][3][4] Aspirin is a typical non-steroidal anti-inflammatory drug with strong anti-inflammatory, anti-thrombotic and analgesic pharmacological effects. Long-term low-dose aspirin (75-150 mg daily) can effectively prevent the incidence of ischaemic cardiovascular and cerebrovascular events. 5,6 However, prophylactic use of low-dose aspirin is currently controversial in patients with COVID-19. The Belgian Federal Agency for Medicines and Health Products released a statement on March 16, 2020 stating that NSAIDs can lead to serious complications.
Equally, a report by French Authorities suggested the use of ibuprofen in COVID-19 patients was detrimental to patient's condition and recovery. 7 Previous experiments suggested that NSAIDs may increase the expression of ACE2 in rats, 8 a pivotal receptor of SARS-CoV-2, which potentially increasing SARS-CoV-2 infectivity.
As aspirin irreversibly inhibits platelet cyclooxygenase, and even causes thrombocytopenia in a percentage of patients, 9 there are concerns that use of aspirin significantly increases the risk of bleeding. Besides, NSAIDs had been shown to alter the function of neutrophils, delaying inflammation and may accelerate the progression of pneumonia. 10 In fact, the side effects of NSAIDs on COVID-19 are largely attribute to its anti-inflammatory effects. Paul Little, professor of primary care research at the University of Southampton suggested that patients on low-dose aspirin for secondary prevention of cardiovascular disease should be advised to continue, noting that aspirin has anti-inflammatory effects only at much higher doses. 11 A recent study showed there was no difference of aspirin usage between the survival and non-survival of COVID-19 patients. 12 To our knowledge, no study reported the relationship between low-dose aspirin and COVID-19 patients with CAD. As an important drug for secondary prevention of coronary artery disease, it is important to explore the relationship between the baseline use of low-dose aspirin and the clinical prognosis of COVID-19 patients.

| Study design and participants
Patients with COVID-19 admitted to the Tongji Hospital of Wuhan (Hubei Province, China) from January 10, 2020, to March 30, 2020, were included in this retrospective analysis. The  The inclusion criteria included COVID-19 patients with pre-existing coronary artery disease, aged over 18 years, who were admitted to Tongji Hospital from January 10, 2020 to March 30, 2020. The exclusion criteria included incomplete medical records, patients with coronary artery disease who received rivaroxaban or dabigatran but not aspirin. Based on their anti-thrombotic drug treatments before hospitalization, the patient cohort was assigned into two groups: the low-dose (75-150 mg daily) aspirin treated group (aspirin, n = 52) and the non-aspirin treated group (non-aspirin, n = 131).

| Data Collection
All clinical data were extracted from patients' electronic medical records. Demographics, medical history, and coexisting comorbidities including CAD, COPD, CKD, diabetes, and hypertension were collected by the attending physician, and vital signs, laboratory findings were recorded on admission.

| Statistical analysis
Normally and abnormally distributed continuous variables were represented by mean ± SD and median (interquartile range), respectively. Categorical variables were represented by number (percentage). Normally and abnormally distributed continuous variables were compared using the Student's t-test and the Mann-Whitney U test, respectively. Categorical variables were compared using the chisquared test or Fisher exact test. Categorical and consecutive variables were evaluated by logistic regression analysis for their ability to predict mortality. A 2-sided α of less than 0.05 was considered statistically significant. Data were analysed using SPSS 21.0 for Windows (SPSS Inc, Chicago, IL, USA).

| RE SULTS
As of March 30, 2020, 2912 consecutive COVID-19 patients were admitted to Tongji Hospital. According to inclusion and exclusion criteria, a total of 2886 patients were included in this retrospective study, including 2703 (93.7%) non-CAD patients and 183 (6.3%) CAD patients. The mean age was 59.1 years and 1402 (49.1%) were men. Patients with CAD had increased risk of all-cause-mortality over non-CAD patients (21.9% vs. 9.1%; P < .001). The characteristics and clinical outcomes of the patients with CAD compared with those without CAD were summarized in the Supplemental Table 1.
Patients with CAD were older (71.2 vs. 58.3; P < .001) and had higher prevalence of comorbidities such as hypertension, diabetes, and chronic kidney disease. In addition, COVID-19 patients with CAD were more seriously ill as they often had liver and kidney function damage and coagulation dysfunction, especially in myocardial damage compared with those without CAD.
The 183 COVID-19 hospitalized patients with CAD were further classified as aspirin group (n = 52) and non-aspirin group (n = 131). As shown in Table 1, the mean age of the studied cohort was 71.2 years, and males made up about half. The total in-hospital mortality of patients with CAD was 21.9%. There was no difference between the aspirin and non-aspirin groups in age, sex, and pre-existing comorbidities. Carefully analysing the laboratory results, there were no different in inflammatory cells count, liver function, renal function related examinations, some cytokines like IL6, IL8 and TNF-α as well as pulmonary imaging performance between aspirin group and non-Aspirin group. Besides, there were also no statistically significant differences in the rate of invasive mechanical ventilation and mortality between the two groups.
To rule out the influence of disease severity on the assessment of the relationship between aspirin and mortality, we further analysed critically severe COVID-19 patients with CAD and divided them into critically severe-aspirin group (mean age 71.3; male 60.0%) and critically severe-non-aspirin group (mean age 72.7; male 59.0%). The characteristics, laboratory results and clinical outcomes of these two groups were summarized in Table 2. There was no difference between critically severe-aspirin group and critically severe-non-aspirin group in most laboratory examination findings as well as the mortality (44.0% vs. 45.9%; P = .872). These data suggested that the use of aspirin was not associated with the high risk of death in COVID-19 patients with CAD in hospital.
To investigate the major risk factors for death of COVID-19 patients with CHD. We further divided these 183 patients into two groups according to their final clinical outcome (survive or die).

The clinical characteristics and treatments between survivors and
non-survivors were analysed and summarized in Table 3. Our results shown that the clinical characteristics of patients from non-survivor group were much worse than survivor group, manifested as older in age, higher proportion of male, more severe inflammation, and organ damage (including myocardial injury). In addition, multivariate logistic regression model analyses were performed for identifying independent correlative factor of mortality of COVID-19 patients with CAD. The results exhibited that the age, proportion of male and the existing complication of CKD were positively correlated with mortality, the usage of low-dose aspirin was not correlated with mortality (Table 4).

| D ISCUSS I ON
The report on March 21, 2020 showed that the mortality of COVID-19 in China was 4.0%, while our data for mortality was 9.6%, mainly because of the patients enrolled in the present study were from Tongji hospital, where admitted more critically ill COVID-19 patients in Wuhan. 14 Besides, the case fatality rate rises rapidly with increasing age or medical comorbidities. 15 Previous research reported that the mortality of COVID-19 patients with cardiovascular disease (CVD) was as much as 10.5%, while our cohort showed that the mortality of patients with coronary artery disease was 21.9%, which was much higher than patients with hypertension, diabetes or COPD. 15 It was reported that the prevalence of CVD in SARS and MERS was 8% and 30% respectively, while varied from 8% to 15% in COVID-19. 2,3 CAD was present in approximately 6.3% of patients in our study which was similar to other literature between 2.5% and 17%. 4,16 Possible explanations for the higher incidence in COVID-19 patients with CAD include elderly, decreased immune system function, increased ACE2, and predisposition. 17 Low-dose aspirin is an most widely used agents for the secondary prevention of cardiovascular disease, and had been proved to effectively reduce the rates of both myocardial infarction and ischaemic stroke. 5,6,18-21 Viral infection was an unstable risk factor for chronic cardiovascular disease. The reduction of intrinsic heart reserve due to chronic cardiovascular disease was further     reported that aspirin had no effect on the rate of overt thrombosis. 30 In fact, coagulation dysfunction in COVID-19 patients is mainly manifested as thrombocytopenia, prolonged prothrombin time and elevated D-Dimer, which are indicators of DIC. Studies have shown that patients with COVID-19 associated coagulopathy who received prophylactic heparin had a lower mortality than patients not receiving anticoagulant treatment. 31 Interestingly, our data showed that     Abbreviations: COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; DBP, diastolic blood pressure; SBP, systolic blood pressure; WBC, white blood cell; RBC, Red blood cell; Neut, neutrophil; Hb, haemoglobin; Lymph, lymphocyte; PLT, platelet; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, Total Bilirubin; Cr, creatinine; BUN, blood urea nitrogen; TC, total cholesterol; TG, Triglyceride; HDL, high density lipoprotein; LDL, low-density lipoprotein; K+, potassium; LDH, Lactate Dehydrogenase; PT, Prothrombin Time; APTT, activated partial thromboplastin time; hs-cTnI, highly sensitive cardiac troponin I; Mb, myoglobin; CK, creatine kinase; CK-MB, creatine kinase-MB; IL6, interleukin 6; IL8, interleukin 8; TNF-α, tumour necrosis factor-α; IL-2R, interleukin 2 receptor; hs-CRP, highly sensitive C reaction protein; Categorical variables were presented as number (percentage) and normally and abnormally distributed continuous variables were represented by mean ± SD and median (first to third quartile, Q1-Q3), respectively P values indicate differences between survivors and non-survivors. P < .05 was considered statistically significant.

TA B L E 3 (Continued)
in COVID-19 patient. Third, the current findings may not be generalizable to all patients with coronary artery disease. Because the study was based on inpatients, it was difficult to reflect the effect of aspirin of outpatient setting or ethnically or geographically diverse populations. Therefore, international large-scale prospective cohort studies and randomized controlled trials are needed to better determine the association between low-dose aspirin and survival in COVID-19.

| CON CLUS IONS
Among patients with coronary artery disease hospitalized by COVID-19, pre-hospitalization treatment with low-dose aspirin was not associated with all-cause mortality of COVID-19 patients with CHD. Despite the possibility of residual confounders, we do not recommend immediate cessation of aspirin in hospitalized patients.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing financial interests or personal relationships that could influence the work reported in this paper.