key: cord-1035984-v5b6wgsv
authors: Rey, Juan R; Caro‐Codón, Juan; Rosillo, Sandra O.; Iniesta, Ángel M.; Castrejón‐Castrejón, Sergio; Marco‐Clement, Irene; Martín‐Polo, Lorena; Merino‐Argos, Carlos; Rodríguez‐Sotelo, Laura; García‐Veas, Jose M.; Martínez‐Marín, Luis A.; Martínez‐Cossiani, Marcel; Buño, Antonio; Gonzalez‐Valle, Luis; Herrero, Alicia; López‐Sendón, José Luis; Merino, José Luis
title: Heart Failure In Covid‐19 Patients: Prevalence, Incidence And Prognostic Implications
date: 2020-08-24
journal: Eur J Heart Fail
DOI: 10.1002/ejhf.1990
sha: 9093d9e9209ee16015e8fa52cd6076cb098d3d3f
doc_id: 1035984
cord_uid: v5b6wgsv

AIMS: Data regarding impact of COVID‐19 in chronic heart failure (CHF) patients and its potential to trigger acute heart failure (AHF) is lacking. The aim of this work was to study characteristics, cardiovascular outcomes and mortality in patients with confirmed COVID‐19 infection and prior diagnosis of HF. Also, to identify predictors and prognostic implications for AHF decompensations during hospital admission and to determine whether there was a correlation between withdrawal of HF guideline‐directed medical therapy (GDMT) and worse outcomes during hospitalization. METHODS AND RESULTS: A total of 3080 consecutive patients with confirmed COVID‐19 infection and at least 30‐day follow‐up were analyzed. Patients with previous history of CHF (152, 4.9%), were more prone to develop AHF (11.2% vs 2.1%; p<0.001) and had higher levels of NT‐proBNP. Also, previous CHF group had higher mortality rates (48.7% vs 19.0%; p<0.001). In contrast, 77 patients (2.5%) were diagnosed of AHF and the vast majority (77.9%) developed in patients without history of HF. Arrhythmias during hospital admission and CHF were main predictors of AHF. Patients developing AHF had significantly higher mortality (46.8% vs 19.7%; p<0.001). Finally, withdrawal of beta‐blockers, mineralocorticoid antagonists and ACE/ARB inhibitors was associated with a significant increase of in‐hospital mortality. CONCLUSIONS: Patients with COVID‐19 have a significant incidence of AHF, entity that carries within a very high mortality. Moreover, patients with history of CHF are prone to develop acute decompensation after COVID‐19 diagnosis. Withdrawal of GDMT was associated with higher mortality.

Coronavirus disease 2019 , the ongoing pandemic responsible for substantial morbidity and mortality all around the globe, has proven to be a multisystemic condition with frequent cardiac manifestations. Cardiovascular (CV) disease and classic CV risk factors are common comorbidities in COVID-19 patients and have been associated with poor outcomes 1 .

Besides, heart failure (HF) is one of the leading causes of morbidity and mortality worldwide and should not be left unattended. Previous knowledge from other respiratory tract infections, such as influenza, has proven virus potential to trigger decompensation of HF patients 2 .

Recent research has focused on the impact of the COVID-19 pandemic in the hospitalization rates, incidence and characteristics of patients attended in specialized HF units 3 , but data regarding prevalence, incidence and prognostic implications of HF in patients with a confirmed diagnosis of SARS-CoV-2 infection is still lacking.

The aim of this work was to study characteristics, cardiovascular outcomes and mortality in patients with confirmed COVID-19 infection and prior diagnosis of HF. We also focused on identifying predictors and prognostic implications of HF decompensation during hospital admission and exploring whether there is an association between withdrawal of guidelinedirected medical therapy (GDMT) and worse outcomes during hospitalization.

We screened all consecutive patients with clinical suspicion of COVID-19 disease attending to the Emergency Department of a tertiary hospital in Madrid, the most affected region in Spain, from March 1 st to April 20 th , 2020. Patients were only included in the study if they had confirmed COVID-19 infection by RNA reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay from nasopharyngeal swab specimens. We specifically aimed to include patients who have completed a follow-up of at least 30 days since microbiological diagnosis.

Therefore, patients who were alive but diagnosed with less than 30 days from the lock of the database were excluded from the present analysis. This study was approved by the Accepted Article This article is protected by copyright. All rights reserved.

Institutional Review Board at our center. Individual written informed consent was waived based on legal standards for national healthcare alarm situations.

Epidemiological, demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic medical records from the index and subsequent hospital admissions using a standardized electronic data collection form. In addition, the central regional healthcare record system, which collects information and medical reports from all public hospitals and primary healthcare centers from Madrid, was reviewed for additional information and follow-up. All data were thoroughly reviewed by a team of 13 cardiologists.

Any disagreements regarding data classification were reviewed by the whole team, and a decision was finally made by consensus. Special care was given to the identification of baseline CV profiles, clinical outcomes and specifically acute heart failure diagnosis.

Chronic heart failure (CHF) was defined as history of previous congestive decompensation or diagnosis of left ventricular systolic dysfunction (LVEF<40%). Acute heart failure (AHF) refers to rapid onset or worsening of symptoms and/or signs of HF during the study period.

Acknowledging the difficulty to distinguish between respiratory and cardiac causes of dyspnea in COVID-19, acute heart failure events were adjudicated on a case-by-case basis by consensus of all investigators. We based our decisions on all clinical information available for each patient: codified HF diagnosis, description of serial physical examinations in the electronic medical records, radiological tests (chest radiography and CT), echocardiographic studies. and NT-proBNP levels according to the recommended cut-off values of the Heart Failure Association of the European Society of Cardiology (ESC) for the diagnosis of AHF: >450 pg/ml in patients below 50 years, >900 pg/ml in patients between 50-75 years and >1800 pg/ml in patients over 75 years 4 .

Categorization of echocardiographic measurements of left ventricular systolic function were based on published recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography 5 . Bleeding events were defined as specified in the Thrombolysis in Myocardial Infarction (TIMI) bleeding classification 6 .

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In order to minimize the risk of selection bias due to severe illness (i.e. hypotension due to septic shock), patients who had medication withdrawn were defined as those who had chronic treatment with angiotensin-converting enzyme inhibitors (ACEi), angiotensin-receptor blocker (ARB), beta-blockers (BB) or mineralocorticoid receptor antagonist (MRA) before hospital admission and did not receive any dose after hospital admission, as confirmed by the central pharmacy computerized information system, and irrespective of their clinical status.

Categorical variables are shown as rates and percentages, and continuous variables as mean  SD or median (IQR) as appropriate. Means for continuous variables were compared using independent group t tests when data were normally distributed, otherwise, Mann-Whitney test was performed. Normality of distributions was assessed using Shapiro-Wilk test. Proportions for categorical variables were compared using the χ2 test or the Fisher exact test, as appropriate. Survival during follow-up was assessed using Kaplan Meier analysis and, when appropriate, the log-rank test. The association of CHF and AHF with mortality during followup was studied using a Cox-proportional hazard model accounting for relevant covariates (age, sex, CV risk factors, coronary heart disease, chronic kidney disease and cerebrovascular disease). Stepwise logistic regression was used to develop a predictive model for AHF during admission, using as candidate variables those which were statistically significant in the univariate analysis. All data were analyzed using the Stata v14.2 statistics package, (StataCorp, College Station, TX, USA). A two-sided p value <0.05 was considered statistically significant for every analysis.

During the study period, 3080 patients with confirmed COVID-19 infection fulfilled our selection criteria and were ultimately included in the present analysis ( Figure 1 , Graphical abstract). Mean age was 62.320.3 years and 1689 (54.8%) were male. Six hundred twentysix patients (20.5%) died during a median follow-up of 59 (50-66) days, the time of death since SARS-CoV-2 diagnosis being 6 (3-12) days (range 0-53).

A total of 152 patients with CHF (4.9% of those with positive RT-PCR) were studied. Of those, 98 (64.5%) had some degree of left ventricular systolic dysfunction prior to Accepted Article This article is protected by copyright. All rights reserved.

diagnosis. The remaining 54 had normalized LVEF after the initiation of guideline-directed medical therapy or had HFpEF with other significant echocardiographic abnormalities such as LV hypertrophy or moderate to severe valvular disease. Baseline characteristics are shown in Table 1 . Patients with history of CHF were older (81.911.9 vs 61.220.1; p<0.001) and had a higher cardiovascular risk profile, as well as different forms of atherosclerotic disease (coronary, cerebrovascular and peripheral). As expected, they were more frequently on treatment with cardiovascular medications. Regarding prescription of dedicated COVID-19 drugs, patients in the CHF group received more hydroxychloroquine (85.5% vs 77.0%; p=0.014) but less tocilizumab and azithromycin.

CHF group had significantly lower glomerular filtration rate (47.923.2 ml/min vs 76.619.7 ml/min; p<0.001) and hemoglobin (12.72.2 g/dl vs 13.61.7 g/dl; p<0.001). No differences were found in proinflammatory makers (ferritin, fibrinogen, C-reactive protein, IL-6) or in Ddimer. However, peak NT-proBNP (1680230726 pg/ml vs 472613530 pg/ml; p<0.001) and hs-Troponin I (433123952 vs 3062646, p<0.001) were significantly higher during hospital admission.

Patients with CHF were more prone to develop clinical findings suggestive of AHF as well as elevation of NT-proBNP above the AHF cut-off. The CHF group developed numerically more thrombotic events than the non-CHF group, but the numbers were small and without significant differences (2.0% vs 3.9%, p=0.234). However, CHF patients received significantly more chronic therapeutic anticoagulant therapy [86 (57.7%) vs 223 (7.7%), p<0.001].

CHF group was less frequently admitted to the intensive care unit (ICU) (1.4% vs 6.4%; p= 0.013) and had a higher mortality during follow-up (48.7% vs 19.0%; p<0.001; Figure 2 left panel). Nevertheless, after adjusting to other relevant covariates, CHF did not reach statistical significance to be identified as an independent predictor of mortality (Supplementary Table   1 ).

During the study period, 77 patients (2.5%) received a diagnosis of AHF (Table 2) . Of these, 47 had documented abnormal NT-proBNP levels according to recommended cut-off for Accepted Article This article is protected by copyright. All rights reserved. diagnosis of AHF, while the remaining 30 did not undergo any NT-proBNP determination during hospital admission (Supplementary table 2 ). Thirty-one AHF patients had available qualitative information regarding point-of-care echocardiographic examinations: 12 with some degree of left ventricular systolic dysfunction, 17 with other pathological findings (such as significant valvular heart disease, pericardial effusion or right ventricular dysfunction) and 2 studies were reported as without significant abnormalities.

Mean age (78.612.6 vs 61.820.3, p<0.001) and cardiovascular risk profile (exception made for the proportion of smokers) were higher in the AHF group. Other associated comorbidities and cardiovascular medications were also more prevalent in this group, although numerically lower than those seen in the CHF group (Table 1) . Interestingly, the vast majority of patients who developed AHF did not have a history of CHF (60, 77.9%). They had more severe presentations of COVID-19, as they had lower levels of oxygen saturation at admission (89.37.6 vs 92.36.2; p<0.001), higher need for supplementary oxygen (20.8% vs 8.9%; p=0.001) and showed a trend towards more frequent bilateral pneumonia.

As expected, peak NT-proBNP (1050820374pg/ml vs 546916118; p<0.001) was higher in AHF patients. Regarding other laboratory findings, significant differences were observed in C-reactive protein and D-dimer. Even though high sensitivity TnI was mildly elevated in both groups, it did not differ significantly (4171683ng/L vs 4585403ng/L; p=0.963). These chronic prescriptions were not associated with worse outcomes after adjusting for relevant covariates (Supplementary Table 4 ).

Regarding the impact of withdrawing guideline-directed medical therapy (GDMT), 32

(35.6%), 15 (16.0%) and 22 (46.8%) patients discontinued ACEi, beta-blockers and MRA respectively during hospital stay. Differences between patients who discontinued HF drugs at admission and those who did not are presented in Table 4 . We only identified statistically significant differences regarding the prevalence of baseline hypertension, treatment with MRA, systolic blood pressure at admission and use of lopinavir/ritonavir. Survival analysis using the log-rank test showed that discontinuation of GDMT was associated with a higher risk of in-hospital death ( Figure 3 ). 

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The present work studied the prevalence and prognostic implications of HF in a large cohort of 3080 consecutive COVID-19 patients. The first key finding was that patients with CHF were at significant risk for acute decompensation after COVID-19 diagnosis. Furthermore, the development of clinical HF in our series was noteworthy and associated with poor outcomes.

SARS-CoV-2 potential to produce myocardial injury, along with impaired cardiopulmonary Regarding other in-hospital complications and given the significant concerns of a higher likelihood of thromboembolic disease in HF patients with COVID-19, it is remarkable that none but three of our CHF patients had a thrombotic event during admission. Indeed, we did not observe differences in thrombotic or inflammatory biomarkers between groups, but these findings may also be related with a higher prevalence of chronic therapeutic anticoagulation among the CHF patients.

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A total of 77 patients (2.5%) developed clinical features of AHF during the study period.

Heart failure has been described after respiratory infections and pneumonia 10 22 or to thromboembolic disease 23 , may also be behind abnormally high levels of NT-proBNP, proinflammatory markers and of course D-dimer.

In the frontline of the COVID-19 pandemic, whether a more liberal determination of cardiac biomarkers may improve early diagnosis and management of AHF, and other cardiovascular complications should be prospectively investigated.

Multivariable analysis confirmed that history of CHF, chronic obstructive pulmonary disease and older age, all three variables associated with a poorer baseline clinical profile, were independent predictors of AHF during hospital admission for COVID-19. Bleeding, a marker of patient vulnerability that usually requires volume resuscitation and administration of blood products, was also independently associated with this complication. However, the strongest predictor of AHF in these patients was the development of atrial arrhythmias during hospital admission. Atrial fibrillation was by far the most common arrhythmia in our series. Its effects may be mediated by multiple and well-known mechanisms, such as loss of atrial mechanical contraction, poor rate control, impaired diastolic filling, irregular R-R intervals and neurohormonal activation 24 . A better knowledge of the conditions related with the

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development of AHF may promote early identification of high-risk patients who may benefit from more dedicated cardiac monitoring and early referral to a multidisciplinary HF management team.

Despite published recommendations from several scientific societies, many patients and physicians chose to stop chronic GDMT. Results of in vitro and animal SARS-Cov-2 models

showing a greater potential of infection due to an over expression of the ACE2 enzyme could not be reproduced in real-life Chinese cohorts 25 or other larger recently publishes series 26, 27 .

Moreover, recent research including a meta-analysis 25, 28 showed that chronic use of reninangiotensin-aldosterone system inhibitors are actually associated with a reduction of inhospital mortality, though none of these studies were originally designed to answer this specific question. Ongoing randomized clinical trials 29 are expected to address the specific hypothesis that withdrawal of RAAS inhibitors in the general population of COVID-19

patients may significantly impact survival.

In the context of chronic heart failure, withdrawal of GDMT in patients with dilated cardiomyopathy who have recovered normal left ventricular ejection fraction (LVEF) was specifically explored in TRED-HF 30 . In this study, up to 40% of the patients had a relapse in the form of either clinical HF or worsened LVEF.

In order to avoid selection bias (i.e. patients discontinuing GDMT due to COVID-19-related progressive clinical deterioration), we defined GDMT withdrawal as the absence of any received dose during hospital admission of HF medication in patients with chronic HF treatment. Our findings should be interpreted cautiously due to the observational nature of the study but strongly suggest that withdrawal of ACE/ARB inhibitors, BB and MRA is associated with higher mortality and argue in favor of the maintenance of these treatments as long as individual benefit is expected. Thus, even if severe presentations of COVID-19 may require temporary reduction or withdrawal of ACE/ARB inhibitors due to hemodynamic or renal deterioration 8 , all efforts should be made at discharge to restore GDMT that have proven to favorably impact the clinical course of HF.

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