key: cord-0843667-1arhjsmt
authors: Sisinni, Antonio; Rossi, Luca; Battista, Antonio; Poletti, Enrico; Battista, Federica; Battista, Rosa Alessia; Malagoli, Alessandro; Biagi, Andrea; Zanni, Alessia; Sticozzi, Concetta; Comastri, Greta; Marrocco-Trischitta, Massimiliano M.; Monello, Alberto; Margonato, Alberto; Bandera, Francesco; Vergara, Pasquale; Guazzi, Marco; Godino, Cosmo
title: Pre-admission acetylsalicylic acid therapy and impact on in-hospital outcome in COVID-19 patients: The ASA-CARE study
date: 2021-10-04
journal: Int J Cardiol
DOI: 10.1016/j.ijcard.2021.09.058
sha: 5cf5f4400a02d8340f6c20d432eec100456cc7f2
doc_id: 843667
cord_uid: 1arhjsmt

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) exhibit high thrombotic risk. The evidence on a potential independent prognostic role of antiplatelet treatment in those patients is limited. The aim of the study was to evaluate the prognostic impact of pre-admission low-dose acetylsalicylic acid (ASA) in a wide series of hospitalized patients with COVID-19. METHODS: This cohort study included 984 COVID-19 patients stratified according to ASA intake before hospitalization: ASA(+) (n = 253) and ASA(−) (n = 731). Patients were included in ASA(+) group if they received it daily in the 7 days before admission. 213 (83%) were on ASA 100 mg daily. Primary endpoint was a composite of in-hospital death and/or need for respiratory support upgrade, secondary endpoints were in-hospital death and need for respiratory support upgrade. RESULTS: Mean age was 72 [62; 81] with 69% of male patients. ASA(+) patients were significantly older, with higher prevalence of comorbidities. No significant differences regarding the degree of respiratory dysfunction were observed. At 30-day Kaplan-Meier analysis, ASA(+) patients had higher survival free from the primary endpoint and need for respiratory support upgrade, conversely in-hospital death did not significantly differ between groups. At multivariate analysis ASA intake was independently associated with a lower probability of reaching primary endpoint (HR 0.697, 95% C.I. 0.525–0.924; p = 0.012). CONCLUSIONS: In COVID-19 patients undergoing hospitalization, pre-admission treatment with ASA is associated with better in-hospital outcome, mainly driven by less respiratory support upgrade.

i i Vita-Salute San Raffaele, Milano, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 7 Division of Cardiology, Cardiovascular and Emergency Department, Guglielmo da Saliceto Hospital, Piacenza, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 8 Division of Cardiology, Cardiovascular and Emergency Department, Guglielmo da Saliceto Hospital, Piacenza, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 9 Division of Cardiology, Cardiovascular and Emergency Department, Guglielmo da Saliceto Hospital, Piacenza, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 10 Division of Cardiology, Cardiovascular and Emergency Department, Guglielmo da Saliceto Hospital, Piacenza, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 11 Division of Cardiology, Cardiovascular and Emergency Department, Guglielmo da Saliceto Hospital, Piacenza, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 12 Clinical Research Unit, Cardiovascular Department, IRCCS Policlinico San Donato, Milan, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 13 Division of Cardiology, Cardiovascular and Emergency Department, Guglielmo da Saliceto Hospital, Piacenza, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 14 Cardiovascular Department, San Raffaele Scientific Institute, Milan, Italy.

i i Vita-Salute San Raffaele, Milano, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 15 Cardiology Unit, IRCCS Policlinico San Donato, Milan, Italy. Università degli studi di Milano, Milan, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 16 Arrhythmias and Cardiac Electrophysiology, San Raffaele Scientific Institute, Milan, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 17 Università degli studi di Milano, Milan, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 18 

Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [1] is responsible for the global pandemic outbreak. At the time of this writing, there have been approximately over 180 million cases reported and more than 3.9 million (~2%) deaths due to COVID-19 across more than 200 countries worldwide. [2] Patients with cardiovascular diseases have been reported to have the highest case fatality. [3] [4] Although most of COVID-19-related physiopathological pathways remain unclear, some evidences suggest that SARS-CoV-2 infection may predispose patients to thrombosis, [5] both in the arterial and venous circulations, [6] due to inflammation, endothelial dysfunction and, finally, pathological platelet hyperactivation. [7, 8] In fact, as Zhang et al. demonstred, [9] SARS-CoV-2 is able to create a spike protein-mediated platelet-ACE2 binding, directly stimulating platelets release of coagulation factors, secretion of inflammatory factors, and formation of leukocyte-platelet aggregates.

Furthermore, endothelial cell infection, as evidenced in some autopsy studies, [10, 11] or the virusinduced inflammatory response, may contribute to systemic microcirculatory function impairment.

The resulting COVID-19-associated endotheliopathy may affect especially, but not only, pulmonary circulation [12] and elicit platelet hyperactivation. For these reasons, antiplatelet therapy, whose impact on outcomes is still under investigation in this subset of patients, may represent an effective therapeutic option. [13] [14] Acetylsalicylic acid (ASA) exerts antithrombotic and anti-inflammatory effects, and it had been demonstrated to play some antiviral activity against deoxyribonucleic and ribonucleic acid viruses. [15] The aim of this study was to evaluate the potential protective effect of Organization. [16] Clinical information including demographics, comorbidities, medical history, laboratory examinations, baseline and in-hospital treatment measures (including respiratory support) and outcomes was collected after discharge by attending physicians (A.S. and E.P. in San Donato Milanese and A.M. in Piacenza). Each patient underwent admission arterial blood gas analysis, complete blood routine test, including hematologic, biochemical and coagulation function, and chest imaging (X-rays and/or computed tomography) evaluation.

Patients were included in ASA group if they were on treatment and they received it daily at least 7 days before admission. [17, 18] ASA treatment was continued during the hospitalization on the same dose as before hospitalization. Patients undergoing orotracheal intubation received ASA by nasogastric tube. Chronic kidney disease (CKD) was defined as Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation-derived estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m 2 . [19] The most intense level of oxygen support during hospitalization (nasal cannula, Venturi mask, nonrebreather mask, noninvasive mechanical ventilation [NMV], An intriguing question involving the scientific community is the definition of the role played by antithrombotic treatment in COVID-19 patients, [7, 20] primarily focusing on anticoagulation and its clinical impact. [21] [22] Considering the lack of a standard of care, dominant related questions are : 1) what is the best antithrombotic strategy (anticoagulant with or without antiplatelet and eventually which specific drug)? and, 2) which kind of clinical benefit to expect from, and primarily which kind of benefit to consider as still useful (freedom from complications and/or survival improvement) for each patient within the broad spectrum of presentation?

The present study is an attempt to provide some potential answers and to make a firm focus on the role of ASA, a therapeutic regimen approved in patients phenotype with multiple cardiovascular comorbidities and more exposed to COVID-19 injury. To the best of our knowledge, this is the largest analysis showing an association between ASA and favourable outcome in COVID-19

patients. The present findings are consistent with a multi-centre study, where ASA was independently associated with decreased risk of mechanical ventilation, intensive care unit admission and finally in-hospital mortality, though in a smaller sample size (412 patients). [23] Conversely, in our analysis ASA failed to predict overall survival. Apparently divergent results may be associated to either patient selection resulting in different baseline clinical features or different level of adjustment for several prognostic confounders. However, since a sub-analysis of the TARGET-COVID study showed an insufficient pharmacodynamic effect of 81 mg daily ASA in a high percentage of COVID-19 patients, most of whom African Americans, [24] it is at least surprising how low-dose (median 81 mg daily) ASA is sufficient to provide such a meaningful clinical effect.

Our results suggest that, although suffering from a similar extent of disease, ASApatients underwent in-hospital progressive clinical deterioration and were in greater need of empirical anti-SARS-CoV-2 therapy and respiratory support, potentially related to a pathological platelet hyperactivation. Through inhibition of synthesis of cyclooxygenase and activation of nuclear factor-κB [13] ASA exerts a simultaneous antiplatelet and anti-inflammatory effect, potentially able to prevent intravascular coagulation and neutrophil-mediated microvascular thrombosis, as showed in animal model. [25] Since platelets may represent a bridge between immune system and thrombosis, therefore the frontline of COVID-19 pathogenesis, [26] antiplatelet therapy may constitute a costeffective, relatively low risk-associated, [27] therapeutic strategy to prevent patients from clinical worsening during SARS-CoV-2 infection in addition to LMWH, especially in non-critically ill patients. Indeed, our analysis identified LMWH as an independent predictor of in-hospital mortality. That is consistent with recently published data deriving from a single multiplatform, randomized, controlled trial suggesting that in the moderately ill patients therapeutic-dose LMWH appeared to increase the probability of survival until hospital discharge. [28] Furthermore, the preprint article reporting the findings of the Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID) trial showed as therapeutic anticoagulation group had a lower incidence of death at 28 days. [29] Therefore, it is reasonable that, rather than a single medication, combination therapies targeting several pathological pathways (e.g., inflammation, coagulopathy, thrombocytopathy and endotheliopathy) are more likely to be successful. should be considered to achieve locally effective concentrations.

To date available data are not sufficient to influence standard of care. Randomized controlled trial, such as the ongoing Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial (NCT04381936), will definitively evaluate whether antiplatelet therapy prevents adverse outcome in patients with COVID-19.

The present study suffers from the following limitations. In view of the observational nature of our analysis, patient selection and ascertainment bias may have influenced event rates. Particularly, identifying study groups according to pre-admission ASA intake represents a selection bias, since patients were on treatment because of the presence of more cardiovascular comorbidities.

Furthermore, we did not account for safety endpoints, such as major bleeding.

Accordingly, our results should be considered as hypothesis generating and need confirmation in further larger observational studies or randomized trials.

In conclusion, in this retrospective analysis of patients with COVID-19 undergoing hospitalization, ASA is associated with a better in-hospital outcome in terms of in-hospital death or need for respiratory support upgrade, whose definitive evidence is mainly supported by the latter. Data are presented as hazard ratio (HR) with 95% confidence interval (CI).

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

A Novel Coronavirus from Patients with Pneumonia in China

COVID-19 Weekly Epidemiological Update

COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives

The Novel Coronavirus Disease (COVID-19) Threat for Patients With Cardiovascular Disease and Cancer

Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans

Thrombosis in Hospitalized Patients With COVID-19 in a New York City Health System

COVID-19 and Thrombotic or

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis

Effects of antiplatelet therapy on the mortality rate of patients with sepsis: A meta-analysis

Prevention or Treatment of Ards With Aspirin: A Review of Preclinical Models and Meta-Analysis of Clinical Studies

Is Acetylsalicylic Acid a Safe and P i Ch i A P i wi h CO D -19 ? Drugs

A new equation to estimate glomerular filtration rate

Antithrombotic therapy in patients with COVID-19? -Rationale and Evidence

Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID)

Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19

Aspirin Use is Associated with Decreased Mechanical Ventilation, ICU Admission, and In-Hospital Mortality in Hospitalized Patients with COVID-19

Bedside thromboelastography to rapidly assess the pharmacodynamic response of anticoagulants and aspirin in COVID-19: evidence of inadequate therapy in a predominantly minority population

The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications

Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19

ACE-I 250 (26) 90 (