key: cord-0972215-djn9drf6
authors: Russo, Vincenzo; Di Maio, Marco; Attena, Emilio; Silverio, Angelo; Scudiero, Fernando; Celentani, Dario; Lodigiani, Corrado; Di Micco, Pierpaolo
title: Clinical impact of pre-admission antithrombotic therapy in hospitalized patients with COVID-19: a multicenter observational study
date: 2020-05-29
journal: Pharmacol Res
DOI: 10.1016/j.phrs.2020.104965
sha: b589d8644e5b5ac8b27e280b8d5546d36dcf6f82
doc_id: 972215
cord_uid: djn9drf6

Little is still known about the clinical features associated with the occurrence of acute respiratory distress syndrome (ARDS) in hospitalized patients with Coronavirus disease 2019 (COVID-19). The aim of the present study was to describe the prevalence of pre-admission antithrombotic therapies in patients with COVID-19 and to investigate the potential association between antithrombotic therapy and ARDS, as disease clinical presentation, or in-hospital mortality. We enrolled 192 consecutive patients with laboratory-confirmed COVID-19 admitted to emergency department of five Italian hospitals. The study population was divided in two groups according to the evidence of ARDS at chest computed tomography at admission. Propensity score weighting adjusted regression analysis was performed to assess the risk ARDS at admission, and death during hospitalization, in patients treated or not with antiplatelet and anticoagulant agents. ARDS was reported in 73 cases (38%), who showed more likely hypertension compared to those without ARDS (57.8 % vs 49.6 %; P = 0.005). Thirty-five patients (18.5%) died during the hospitalization. Not survived COVID-19 patients showed a statistically significant increased age (77 ± 8.31 vs 65.57 ± 8.31; P = 0.001), hypertension (77.1% vs 53.5%; P = 0.018) and coronary artery disease prevalence (28.6% vs 10.2%; P = 0.009). Both unadjusted and adjusted regression analyses showed no difference in the risk of ARDS at admission, or death during hospitalization, between patients treated or not with antiplatelets or anticoagulants. Pre-admission antithrombotic therapy, both antiplatelet and anticoagulant, does not seem to show a protective effect in severe forms of COVID-19 with ARDS at presentation and rapidly evolving toward death.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel highly pathogenic human coronavirus recently recognized as the cause of the coronavirus disease 2019 .

The outbreak sparked in Wuhan, capital city of Hubei province in China, and spread rapidly to other countries, reaching devastating pandemic proportion (1) . Italy is the one of the hardest hit countries by COVID-19, with more than 200,000 laboratory-confirmed cases by May 2, 2020 (2) .

The clinical course of COVID-19 may be complicated by several life-threatening conditions including sepsis, respiratory failure, heart failure, acute kidney and cardiac injury, and septic shock (3) . Little is still known about the patient clinical characteristics predisposing to the occurrence of these life-threatening conditions. Acute distress respiratory syndrome (ARDS) is one of the most frequent encountered complication of COVID-19, and has been associated with significantly lower patients' survival during hospitalization. Although its pathophysiology is not completely understood, the interplay between inflammation and coagulation seems to have a central role (4) .

Whether anti-inflammatory drugs and anticoagulants might influence the onset of ARDS in has not yet been investigated.

The aim of this multicenter study was to evaluate the prevalence of antithrombotic therapies at admission in patients with COVID-19 and the potential association between antithrombotic therapy and ARDS, as disease clinical presentation, or in-hospital mortality. At admission, all patients underwent medical history, physical examination and laboratory evaluation. Chest X-Ray and/or Computed Tomography (CT) scan were also performed to rule out pneumonia in one or multiple sites. The COVID-19 population was divided in two groups according to the diagnosis of isolated pneumonia or pneumonia with ARDS and according to inhospital mortality. ARDS diagnosis was defined according to the Berlin definition (5) .

The prevalence and the type of antithrombotic therapy have been compared between these groups. Discontinuation of antithrombotic therapy during hospitalization was considered as an exclusion criterion. The institutional ethics committee approved the protocol. Verbal and written informed consent for participation was provided for all patients.

Distribution of continuous data was tested with the Kolmogorov-Smirnov and the Shapiro-Wilk test. Normally distributed variables were expressed as mean ± standard deviation (SD), whereas non-normal distributed ones as median and interquartile range (IQR). Categorical variables were reported as numbers and percentages. Continuous normally-distributed variables were compared by using the Student t-test; differences between non-normally distributed variables were tested with the Mann-Whitney U test. Categorical variables were compared with chi-squared test, or Fisher exact test, when appropriate. The unadjusted and adjusted risk ratios (RR) for the outcomes of interest were calculated using logistic regression models and presented as RR with their 95% confidence intervals (CI). We used propensity score weighting to account for potential selection bias in treatment assignment between the two study groups (average treatment effect weights). The propensity score model was developed incorporating all pre-procedural covariates potentially related to the outcome and/or treatment decision regardless of their statistical significance or collinearity with other variables included in the model. The following baseline covariates were J o u r n a l P r e -p r o o f included in the propensity score model: age, smoke, chronic obstructive pulmonary disease (COPD), hypertension, diabetes, coronary artery disease (CAD), heart failure, obesity, dyslipidemia, stroke, and chronic kidney disease (CKD). After weighting, standardized mean differences were calculated to assess the balance for all covariates included in the propensity score model; values higher than 0.10 were considered statistically significant for differences among groups.

For all test, a p value <0.05 was considered statistically significant. Analysis were performed by using R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria).

The characteristics of the study population were reported in Table   2 ). Figure 1 shows the proportion of death according to pre-admission antiplatelet and anticoagulant therapy.

In spite of the significant differences among survived and not survived COVID-19 patients in baseline characteristics, the inverse probability weighting produced a good covariate balance, with absolute standardized differences less than 10% for all variables. Figure 2 shows graphically how the antiplatelet and anticoagulant arms were more balanced in terms of allocation probability respect to patients were not taking anti-thrombotic drugs at admission. Unadjusted and adjusted regression models for the risk of ARDS and death according to pre-admission antithrombotic therapy was reported in Table 3 . Pre-admission antithrombotic therapy with antiplatelets or anticoagulants did not result associated with increased risk of ARDS at admission and in-hospital mortality in COVID-19 patients.

The main findings of the present study can be summarized as follows: a large proportion of patients admitted for COVID-19 is on treatment with antithrombotic agents; antithrombotic therapy stratified patients with older age and higher prevalence of comorbidities; patients who did not survived were older and showed higher prevalence of comorbidities; neither antiplatelet therapy nor anticoagulant therapy affected the risk of severe clinical presentation as ARDS at admission or death during hospitalization.

Among our study population including Italian hospitalized COVID-19 patients, we confirmed the epidemiological association between cardiovascular risk (CV) factors and the individual susceptibility to SARS-CoV2 infection, as previously described in Chinese and American cohort studies (6, 7) . Particularly, hypertension, diabetes and coronary artery disease J o u r n a l P r e -p r o o f were the most prevalent comorbidities. Moreover, as previously showed by early Chinese data (8, 9) , the prevalence of CV diseases, in particular hypertension, was significantly increased in critically ill COVID-19 patients with ARDS compared to those with milder forms of disease and, in the same way, hypertension and CAD were significantly increased in non-survived COVID-19 patients compared to survivors.

Among our study population, the AF prevalence, as preexisting comorbidity at admission, was 12.5%, higher than expected in general population (10) ; however, no difference in AF prevalence has been shown in COVID-19 patients with more severe form of disease characterized by ARDS and poor clinical outcome.

The pathogenesis of ARDS in the clinical context of COVID-19 may be related to the direct effect of SARS-CoV-2 on alveolar epithelial cells and to indirect effects of infection-related hypoxia, both conditions predisposing to thrombotic events. Moreover, preliminary reports (11, 12) suggest that a severe inflammatory response and disseminated intravascular coagulation (DIC) may occur in COVID-19 patients predisposing to microvascular pulmonary thrombosis.

Based on the pathophysiological hypothesis that COVID-19-induced ARDS patients may be driven by microvascular thrombotic processes, we decided to investigated if the pre-admission antithrombotic therapy, including both antiplatelet and anticoagulant drugs, might impact on the clinical course and prognosis of hospitalized COVID-19 patients.

In the present analysis, antithrombotic therapy before admission did not influence the clinical presentation COVID-19 in terms of ARDS and in-hospital mortality. These results suggest that the pathophysiology of microvascular pulmonary thrombosis in the clinical context of COVID-19induced pneumonia is not influenced by pre-admission antithrombotic treatment, probably due to the complex interplay between clotting system activation and the SARS-CoV2 immuno-mediated inflammatory response, two processes that mutually reinforce each other. 

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Patients Hospitalized With COVID-19 in the New York City Area

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Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

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Age, mean years (SD)

Anticoagulant Therapy, n (%)

Age, mean years (SD)

Atrial fibrillation, n (%)

Anticoagulant Therapy, n (%)

CAD, coronary artery disease

CKD, chronic kidney disease