key: cord-0714809-4z7kr0rf
authors: Ruocco, Gaetano; McCullough, Peter A.; Tecson, Kristen M.; Mancone, Massimo; De Ferrari, Gaetano M.; D'Ascenzo, Fabrizio; De Rosa, Francesco G.; Paggi, Anita; Forleo, Giovanni; Secco, Gioel G.; Pistis, Gianfranco; Monticone, Silvia; Vicenzi, Marco; Rota, Irene; Blasi, Francesco; Pugliese, Francesco; Fedele, Francesco; Palazzuoli, Alberto
title: Mortality Risk Assessment Using CHA(2)DS(2)-VASc Scores In Patients Hospitalized With COVID -19 Infection
date: 2020-09-28
journal: Am J Cardiol
DOI: 10.1016/j.amjcard.2020.09.029
sha: 2535095a8757e3dbab9eba9be5f3a33ea6ba53fd
doc_id: 714809
cord_uid: 4z7kr0rf

Early risk stratification for complications and death related to COVID-19 infection is needed. Because many patients with COVID-19 who developed acute respiratory distress syndrome have diffuse alveolar inflammatory damage associated with microvessel thrombosis, we aimed to investigate a common clinical tool, the CHA(2)DS(2)-VASc, to aid in the prognostication of outcomes for COVID-19 patients. We analyzed consecutive patients from the multicenter observational CORACLE registry, which contains data of patients hospitalized for COVID-19 infection in 4 regions of Italy, according to data-driven tertiles of CHA(2)DS(2)-VASc score. The primary outcomes were inpatient death and a composite of inpatient death or invasive ventilation. Of 1045 patients in the registry, 864(82.7%) had data available to calculate CHA(2)DS(2)-VASc score and were included in the analysis. Of these, 167(19.3%) died, 123(14.2%) received invasive ventilation, and 249(28.8%) had the composite outcome. Stratification by CHA(2)DS(2)-VASc tertiles (T1: ≤1; T2: 2-3; T3: ≥4) revealed increases in both death (8.1%, 24.3%, 33.3%, respectively;p<0.001) and the composite endpoint (18.6%, 31.9%, 43.5%, respectively;p<0.001). The odds ratios(ORs) for mortality and the composite endpoint for T2 patients versus T1 CHA(2)DS(2)-VASc score were 3.62(95% CI:2.29-5.73,p<0.001) and 2.04(95% CI:1.42-2.93, p<0.001), respectively. Similarly, the ORs for mortality and the composite endpoint for T3 patients versus T1 were 5.65(95% CI:3.54-9.01,p<0.001) and 3.36(95% CI:2.30-4.90,p<0.001), respectively. In conclusion, among Italian patients hospitalized for COVID-19 infection, the CHA(2)DS(2)-VASc risk score for thromboembolic events enhanced the ability to achieve risk stratification for complications and death .

Coronavirus disease 2019 (COVID-19) is a viral infection causing acute respiratory distress syndrome (ARDS) and was initially observed in December 2019 in Wuhan, China. 1 One of the concerning features of COVID-19 patients is the development of severe coagulopathy. Indeed, a recent report from Wuhan revealed that among patients who died from COVID-19, 71.4% met criteria for disseminated intravascular coagulation (DIC). Some researchers argue that thrombotic derangement is related to multi organ damage disease or that it is a direct effect of infection on hepatic function. Accordingly, recent studies found a high incidence (25%) of venous thromboembolism (VTE) in COVID-19 patients. 2, 3 Additionally, elevated levels of D-dimer and fibrinogen have been reported in COVID-19 patients, which appear to be associated with negative outcomes. 4 Further, others have demonstrated that COVID-19 patients treated with tissue plasminogen activator (tPA) and heparin experienced more favorable outcomes compared to untreated patients, had improvements in respiratory compliance (expressed by PaO2/FiO2 ratio), and had reductions in D-dimer serum levels. 5, 6 These findings may support the hypothesis that the DIC was of a thrombotic origin instead of bleeding diathesis or multiorgan damage. 2 However recent data of COVID-19 patients' autopsies reveal extensive areas of inflammatory infiltration associated with interstitial oedema and thrombotic lesions in microvessels and in some cases, even massive pulmonary embolism. [7] [8] [9] On the basis of these findings, we sought to investigate thromboembolic risk in COVID-19 patients by utilizing CHA(2)DS(2)-VASc. Specifically, in this case series, we explored the relationship between CHA(2)DS(2)-VASc score and the need for mechanical ventilation and/or inpatient mortality.

We used the CORACLE registry, which include relevant data on COVID-19 patients hospitalized in 4 regions of Italy, to perform this analysis. All patients were at least 18 years old, were admitted to the hospital on or after February 22, 2020, and had COVID-19 infection, confirmed using nose or throat swab testing with real-time reverse transcription polymerase chain reaction. All patients received at least 2 venous administrations of low molecular weight heparin (LMWH) as thromboembolism prophylaxis. We chose to restrict this analysis to patients having data available on admission to calculate CHA(2)DS(2)-VASc score, as well as having a known inpatient mortality status (i.e. discharged alive or died in the hospital) at the time of analysis. At hospital admission, all patients gave their written consent to data collection anonymously. The study was conducted according to the principles outlined in the Declaration of Helsinki. This work was approved by the ethical committee of Turin (CORACLE registry: epidemiology clinical characteristics and therapy in real life patients affected by Sars-Cov-2).

The CHA(2)DS(2)-VASc score was calculated as follows: 1 or 2 points in each category as follows: age within 65-74 years = 1, age ≥75 years = 2, female = 1, presence of hypertension = 1, presence of diabetes = 1, previous myocardial infarct or peripheral artery disease = 1, previous stroke = 2, diagnosis of congestive heart failure = 1. Hence, CHA(2)DS(2)-VASc scores range from 0 to 9 points and a score ≥2 is associated with thromboembolic risk, indicating the need for anticoagulation in atrial fibrillation (AF) patients. 10 We analyzed patients according to data-driven tertiles of CHA(2)DS(2)-VASc scores.

Age and CHA(2)DS(2)-VASc scores were skewed and are presented as median [25 th percentile -75 th percentile]. In order to more clearly evaluate risk, we categorized CHA(2)DS(2)-VASc according to data-driven tertiles. Categorical variables are reported as counts and proportions. Differences in patient characteristics across CHA(2)DS(2)-VASc tertiles were assessed via the Kruskal-Wallis Test and Chi-Square test, as appropriate. Receiver operating characteristic (ROC) curve analysis was employed to quantify the prognostic power of CHA(2)DS(2)-VASc score for death and also for the composite endpoint (death and/or receiving invasive ventilation). We additionally examined crude odds ratios (OR) for death for individual CHA(2)DS(2)-VASc components: age category, gender, hypertension, diabetes mellitus, ischemic heart disease, stroke, and heart failure (HF). Analyses were performed using SPSS version 20.0.

We collected data from 1045 patients in the CORACLE registry. Of these patients, 864

(82.7%) had data required to calculate CHA(2)DS(2)-VASc score and were included in this analysis. Our sample had a median age of 65 [53-76] years and a median CHA(2)DS(2)-VASc score of 2 [1] [2] [3] . Males were more prevalent than females (62.2%). The rates of comorbidities were as follows: hypertension 48.6%, diabetes 15.7%, ischemic heart disease 11.2%, chronic obstructive pulmonary disease 9.4%, stroke 7.6% and HF 6.1%. Data-driven tertiles of CHA(2)DS(2)-VASc scores were as follows T1: ≤1, T2: 2-3, T3: ≥4. Patient characteristics according to CHA(2)DS(2)-VASc tertiles are shown in Table 1 . ischemic heart disease/ peripheral artery disease (OR: 2.42, 95% CI: 1.56-3.77, p<0.001) were all significantly associated with death ( Figure 3 ).

To our knowledge, this is the first study to stratify COVID-19 patients according to CHA(2)DS(2)-VASc score. Our findings indicate that in this Italian population, patients with higher CHA (2) cases showed that about 20% of patients need ICU admission with invasive respiratory management. Among severe ARDS cases, alterations in blood-clotting have been observed, with possible microthrombi occurring within the tiny blood vessels interacting with the lung alveoli, preventing capillaries from filling, and leading to impaired gas exchange. 12 Therefore, there is an unmet need for the early recognition of these severe/critical patients before ARDS occurs.

Notably, others have attempted to build prediction models in order to better risk stratify COVID-19 patients. Two Chinese reports identified the following the following variables as being related to a poorer prognosis: advanced age, high C-Reactive Protein levels, and large comorbidity burden. 13 Similarly, a retrospective analysis of 487 patients revealed that older age, male gender, and hypertension were all independent predictors of severe COVID-19 disease requiring hospital admission. 14 Further, a retrospective, multicentre cohort study of 191 Chinese COVID-19 patients demonstrated that older age, higher Sequential Organ Failure Assessment score, and D-dimer > 1 μg/mL were independently associated with in-hospital death, revealing significant power to detect high risk subjects. 4 Similarly, other reports have demonstrated that increased levels of D-dimer and fibrinogen, as well as lower levels of platelets, are indicative of severe infection. 2, [15] [16] [17] [18] These findings have prompted the use of tPA and heparin, which have been associated with decreased COVID-19 disease severity. 5, 6 Other laboratory markers such as PAI-I, platelet counts, interleukins, have been analysed in order to initially identify patients with higher risk of complications. Unfortunately, none of these variables are recognized in most common scores used for thromboembolic events prediction. Our approach using the CHA(2)DS(2)-VASc score has the advantages over these prior attempts of risk stratification in that it is simple, can be done upon admission, and is not dependent on or confounded by laboratory or other measurements. However, we cannot assert that current score may be applicable in all COVID populations presenting with different clinical characteristics, CV risk, and respiratory disease involvement. Accordingly, a larger sample size from the UK showed some discrepancies in terms of baseline risk profile and mortality rate compared to our sample size, and CHA(2)DS(2)-VASc should be tested in a larger population before being systematically applied. 19 However, comparing ventilated patients with those of the cited study, the mortality risk appears quite similar. 20 This percentage reflects the mortality rate of the larger Italian analysis of ICU patients in Lombardy (1591 patients). Indeed, Grasselli et al, reported a 26% mortality rate among ICU patients. Patients who did not receive invasive ventilation may have died due to a contraindication of invasive ventilation, resulting in respiratory deterioration. 21 It should be biologically plausible that the CHA(2)DS(2)-VASc score would predict outcomes for patients with COVID-19 infection. Some reports demonstrated that sudden clinical deterioration is often linked to increased intravascular coagulation, and several concerns were recently raised regarding the possible relation between COVID-19 infection and blood-clotting alteration. 11 However, no data exist regarding the prophylactic use of anticoagulant drugs, although COVID-19 patients are prone to thromboembolic events and DIC. 2, 3, [22] [23] [24] The mechanisms underlying infection, inflammation and coagulopathy in COVID-19 disease are poorly understood, but likely reflect the course of similar viral infections, such as SARS and ebola. 2 In normal conditions, the coagulation cascade activation recognizes three different pathways: the antithrombin system, the endothelial protein C system, and tissue factor (TF) pathway inhibitor. In acute sepsis, all these pathways are inhibited due to of impaired synthesis, ongoing consumption and proteolytic degradation leading to a complete derangement of endothelial function in peripheral vessels and capillary district. Overexpression of tissue factor, activation of C protein system, and the inhibition of physiological fibrinolysis processes represent the key mechanisms involved in this coagulopathy. Indeed, viral infection and subsequent immune response mediated by macrophages and T lymphocytes generate an overexpression of immune mediators such as cytokines and chemokines (IL-1,IL-6,IL-8, IL-21, TNF-β and MCP-1). which activate endothelium. Therefore, TNF, IL-6 and IL-1 amplify the pro-coagulant activity stimulating both thrombi formation and increased vascular permeability due to its endothelial effects. [25] [26] [27] [28] In the lung, excretion of fibrin is related to alveolar damage through hyaline membrane deposition, which lead to alveolar collapse.

Together with alveolar collapse, microvascular thrombi impair gas exchange, which results in ARDS and acute lung injury. Although, the CHA(2)DS(2)-VASc is primary designed for embolic risk prevention in AF, the prothrombotic state related to COVID-19 infection likely involves both micro and macro vascular pulmonary district reflecting diffuse endothelial dysfunction. This procoagulant activity may also be systematically present in several organs, and it could also facilitate the risk of large vessel thrombo-embolic disease. 29 Therefore, the clinical scenario includes an initial viral infection of the respiratory tract experiencing the first host immune response. In specific conditions in which inflammation is associated with the cytokine storm and the immune response upregulation, a pro-coagulation state prevails. 29 Our study has all the limitations of retrospective studies of prospectively collected data. A detailed laboratory analysis contemporarily investigating D-dimer, fibrinogen, and plasminogen levels was not available for study. Accordingly, a more detailed score including both clinical and laboratory variables deserve a specific analysis and validation and it could become much more appropriate for risk assessment definition in this setting. CHA (2) 

DS(2)-VASc scores had higher rates of mechanical ventilation or death

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

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Online ahead of print. FIGURE HEADERS Figure 1. Rates of death and composite endpoint (death or invasive ventilation) according to tertiles of CHA(2)DS(2)-VASc scores

Receiver Operating Characteristic curves for death and the composite endpoint of death or invasive ventilation for the predictor of CHA(2)DS(2)-VASc score (ROC curve analysis was employed to quantify the prognostic power of CHA(2)DS(2)-VASc score for death and also for the composite endpoint

Forest plot of odds ratios for mortality of individual CHA(2)DS(2)-VASc components (crude OR for death for individual CHA(2)DS(2)-VASc components: age category, gender, hypertension, diabetes mellitus, ischemic heart disease, stroke, and heart failure)

Continuous variables: median

PAD = peripheral artery disease (2,5% of total population)

ACEi = angiotensin II convertingenzyme inhibitor

ARB = aldosterone receptor blocker Superscripts indicate missing data