key: cord-0944024-6gxw2mhq authors: Haji Aghajani, Mohammad; Moradi, Omid; Amini, Hossein; Azhdari Tehrani, Hamed; Pourheidar, Elham; Rabiei, Mohammad M.; Sistanizad, Mohammad title: Decreased in‐hospital mortality associated with aspirin administration in hospitalized patients due to severe COVID‐19 date: 2021-05-08 journal: J Med Virol DOI: 10.1002/jmv.27053 sha: e807e5306adfd72bc96d850e8df734e32bdd6678 doc_id: 944024 cord_uid: 6gxw2mhq Hypercoagulability and thrombosis caused by coronavirus disease 2019 (COVID‐19) are related to the higher mortality rate. Because of limited data on the antiplatelet effect, we aimed to evaluate the impact of aspirin add‐on therapy on the outcome of the patients hospitalized due to severe COVID‐19. In this cohort study, patients with a confirmed diagnosis of severe COVID‐19 admitted to Imam Hossein Medical Center, Tehran, Iran from March 2019 to July 2020 were included. Demographics and related clinical data during their hospitalization were recorded. The mortality rate of the patients was considered as the primary outcome and its association with aspirin use was assessed. Nine hundred and ninety‐one patients were included, of that 336 patients (34%) received aspirin during their hospitalization and 655 ones (66%) did not. Comorbidities were more prevalent in the patients who were receiving aspirin. Results from the multivariate COX proportional model demonstrated a significant independent association between aspirin use and reduction in the risk of in‐hospital mortality (0.746 [0.560–0.994], p = 0.046). Aspirin use in hospitalized patients with COVID‐19 is associated with a significant decrease in mortality rate. Further prospective randomized controlled trials are needed to assess the efficacy and adverse effects of aspirin administration in this population. rate of the patients was considered as the primary outcome and its association with aspirin use was assessed. Nine hundred and ninety-one patients were included, of that 336 patients (34%) received aspirin during their hospitalization and 655 ones (66%) did not. Comorbidities were more prevalent in the patients who were receiving aspirin. Results from the multivariate COX proportional model demonstrated a significant independent association between aspirin use and reduction in the risk of in-hospital mortality (0.746 [0.560-0.994], p = 0.046). Aspirin use in hospitalized patients with COVID-19 is associated with a significant decrease in mortality rate. Further prospective randomized controlled trials are needed to assess the efficacy and adverse effects of aspirin administration in this population. pandemic, different aspects of the disease pathology have been reported. Studies showed the significant effect of COVID-19 on increasing the risk of hypercoagulability and thrombosis that are associated with increased mortality. [1] [2] [3] [4] Although the incidence rate of thrombotic complications of COVID-19 was initially reported 25%-42%, recent studies showed a higher prevalence of up to 85% despite using pharmacological thromboprophylaxis. 1, 2, 5 The benefit of using the anticoagulant to decrease the risk of these complications and improve the survival of the patients with COVID-19 was confirmed by many studies 3, 6, 7 but data about the effect of antiplatelet agents on these complications are limited. 2, 7 Aspirin has been commonly recommended for the primary prevention of atherosclerotic cardiovascular diseases in high-risk patients. 2, 8 As the thromboinflammatory syndrome is one of the suggested pathophysiological hypotheses in COVID-19, 5,7 the anti-inflammatory effect of aspirin by the inhibition of cyclooxygenase-1 should also be considered as the potential benefit in the prevention of thrombotic complications of COVID-19 in addition to its antiplatelet effect. 2, 5 In this study, we aimed to evaluate the impact of aspirin add-on therapy on the outcome of the patients hospitalized due to severe COVID-19. This retrospective cohort study was conducted at Imam Hossein Medical Center, a tertiary teaching hospital, affiliated with Shahid Beheshti University of Medical Sciences in Tehran, Iran. Patients with confirmed severe to critical COVID-19, based on reverse transcriptase-polymerase chain reaction (rt-PCR), who admitted to the hospital from March 2019 to July 2020 were evaluated. 9 The study was performed following the declaration of Helsinki and the board of ethics committee approval. Age younger than 18 years old and diagnosis of COVID-19 based on clinical criteria without positive rt-PCR results were considered as exclusion criteria. Included patients in the study were divided into two groups, patients who received aspirin at the dose of 80 mg per day from the first day of admission during their hospitalization period, and subjects who did not. Baseline characteristics of enrolled patients including age, sex, body mass index (BMI), past medical and habitual history, and other related clinical data were recorded. Laboratory data regarding complete blood cell count, inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin were extracted from the records. Besides agents used for the treatment of COVID-19, administration of beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) during hospitalization were also recorded. All patients in both groups received the standard of care in the intensive care unit including oxygen supplementation and ventilation support, rehydration and electrolyte correction, vasoactive agents and antibiotic administration, and renal replacement support as needed. All support was provided by the attending intensive care unit specialists for all patients. Also, they received nutrition support provided by the center nutritionist to optimize their feed and nutrition plan based on their clinical status. The mortality rate of patients was assessed as the primary outcome. The need for mechanical ventilation and duration of hospitalization were also considered as secondary outcomes. All patients were stratified based on their recorded data on aspirin use during their hospitalization. Quantitative data were analyzed for nonparametric distribution by the Kolmogorov-Smirnov test. Variables with parametric distribution were reported by means ± standard deviation and nonparametric distributed variables by median (interquartile range [IQR]). Data description for qualitative variables conducted using frequency (percentage). Independent t-test or Mann-Whitney test considered for bivariable analysis of parametric and nonparametric continuous variables, respectively. χ 2 test considered for analysis of categorical variables. The p-value of less than 0.05 was considered significant. 10 Adjustment of the model for two medication classes including ACEIs/ARB and beta-blockers and medications used to treat COVID-19, that is, antiviral agents and corticosteroids were considered. 11, 12 Scaled Schoenfeld residual test with the significance of p-value of less than 0.05 is considered to assess the proportional hazard assumption in COX analysis. The proportional hazard with the 95% confidence interval was reported. A p-value of less than 0.05 was considered significant. In a duration of 5 months, 991 patients were included in the study, of that 544 patients (54.89%) were males and 447 ones (45.10%) were females. The mean age of patients was 61.640 ± 17.003 years. Baseline demographics and clinical characteristics of the patients are demonstrated in Table 1 . Three hundred and thirty-six patients (34%) received aspirin during their hospitalization whereas 655 (66%) did not. Of those who received aspirin, 202 patients (60%) were taking the medication before hospital admission, and aspirin was initiated for the rest of them on the first day of hospital admission. Patients received aspirin during their hospitalization period for the median duration of 7 days. Regarding demographics, patients who received aspirin were older (p < 0.001) but no significant differences were observed in gender distribution and obesity between the two groups. We also did not detect any significant differences in initial vital signs between the two groups except for systolic blood pressure which was significantly higher in the group receiving aspirin (p = 0.011). Hypertension, diabetes, chronic kidney disease, and coronary artery disease were more prevalent in patients who received aspirin (p < 0.001), but there was no significant difference of the patients who received aspirin and in 338 (51.6%) of them who did not (p = 0.123). Furthermore, fever was not significantly less prevalent in the patients who were receiving aspirin before hospital admission (p = 0.369). Fever was reported in 95 (47.1%) of patients who were receiving aspirin before hospitalization compared with 107 (53.0%) of patients who did not receive aspirin. Baseline laboratory data did not show any significant difference between the two groups except in ESR, serum urea, and creatinine levels ( Table 1) . Patients received hydroxychloroquine, lopinavir/ritonavir, corticosteroids, interferon beta 1a, remdesivir, and favipiravir for treatment of COVID-19. No significant differences were observed in the distribution of used medication between the two groups of the study. In the comparison of the outcomes between patients who received aspirin and those who did not, the need for mechanical ven- In this cohort study, based on results from the bivariable analysis, the mortality and hospital length of stay were higher in the group of patients who received aspirin. By considering the higher prevalence of underlying conditions and older age in the aspirin group, it could be expected that these patients may experience a more severe course of the disease and a higher rate of mortality. By adjustment of the effect of underlying conditions and demographics, which could be related to the higher rate of mortality and severity of the disease course, the analysis revealed that aspirin has a protective effect on mortality. Vascular and thrombotic events are relatively common in severe COVID-19. Some studies reported the association between severe COVID-19 and increased risk of endothelial damage, coagulation disorders, thromboembolic events, and severe pulmonary parenchymal damage due to the conformation of micro thrombosis, 13, 14 and the autopsy showed megakaryocytes platelet-rich thrombi in the heart, lung, and kidneys of these patients. 15, 16 Also, these patients are prone to dehydration and accurate examination should be performed to diagnose the possible dehydration as a possible cause of hypercoagulopathy. Therefore, inhibition of platelet aggregation by aspirin could be helpful. 14 Different mechanisms for the protective role of aspirin in COVID-19 could be proposed 2 To the best of our knowledge, our study is the largest study for the evaluation of aspirin effect in outcomes of the patients with severe to critical COVID-19, based on a multivariable model. We revealed that aspirin use was associated with a decrease in mortality. The main limitations of our study were the retrospective pattern of the study and lack of data about the probable adverse effect of aspirin, such as bleeding components. In conclusion, based on the result of our study, in patients who received aspirin, a relevant underlying condition such as hypertension, diabetes, and coronary artery disease was more prevalent. These patients had a more severe course of the disease and a longer duration of hospitalization. By adjustment of the effect of underlying conditions and confounding factors, aspirin use in severe hospitalized COVID-19 patients is independently associated with a 25% decrease in mortality rate. So, by considering all the probable described mechanisms and the results of other studies in this regard, we recommend using aspirin during the hospital stay for all patients with the diagnosis of severe COVID-19. This study was supported via the Deputy of research and technology, Shahid Beheshti University of Medical Sciences, Iran. No specific grants from funding agencies, commercial, and non-profit sectors were received. 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