key: cord-0870470-tkdzt5ol
authors: Peltzer, Bradley; Manocha, Kevin K.; Ying, Xiaohan; Kirzner, Jared; Ip, James E.; Thomas, George; Liu, Christopher F.; Markowitz, Steven M.; Lerman, Bruce B.; Safford, Monika M.; Goyal, Parag; Cheung, Jim W.
title: Outcomes and mortality associated with atrial arrhythmias among patients hospitalized with COVID‐19
date: 2020-10-14
journal: J Cardiovasc Electrophysiol
DOI: 10.1111/jce.14770
sha: 0591d3cfacdc9a1555b692ca05620c3480f63a33
doc_id: 870470
cord_uid: tkdzt5ol

INTRODUCTION: The impact of atrial arrhythmias on coronavirus disease 2019 (COVID‐19)‐associated outcomes are unclear. We sought to identify prevalence, risk factors and outcomes associated with atrial arrhythmias among patients hospitalized with COVID‐19. METHODS: An observational cohort study of 1053 patients with severe acute respiratory syndrome coronavirus 2 infection admitted to a quaternary care hospital and a community hospital was conducted. Data from electrocardiographic and telemetry were collected to identify atrial fibrillation (AF) or atrial flutter/tachycardia (AFL). The association between atrial arrhythmias and 30‐day mortality was assessed with multivariable analysis. RESULTS: Mean age of patients was 62 ± 17 years and 62% were men. Atrial arrhythmias were identified in 166 (15.8%) patients, with AF in 154 (14.6%) patients and AFL in 40 (3.8%) patients. Newly detected atrial arrhythmias occurred in 101 (9.6%) patients. Age, male sex, prior AF, renal disease, and hypoxia on presentation were independently associated with AF/AFL occurrence. Compared with patients without AF/AFL, patients with AF/AFL had significantly higher levels of troponin, B‐type natriuretic peptide, C‐reactive protein, ferritin and d‐dimer. Mortality was significantly higher among patients with AF/AFL (39.2%) compared to patients without (13.4%; p < .001). After adjustment for age and co‐morbidities, AF/AFL (adjusted odds ratio [OR]: 1.93; p = .007) and newly detected AF/AFL (adjusted OR: 2.87; p < .001) were independently associated with 30‐day mortality. CONCLUSION: Atrial arrhythmias are common among patients hospitalized with COVID‐19. The presence of AF/AFL tracked with markers of inflammation and cardiac injury. Atrial arrhythmias were independently associated with increased mortality.

Since the initial description of cases of severe acute respiratory syndrome-novel coronavirus 2 (SARS-CoV-2) infection in late 2019, a total of almost 24 million confirmed cases with over 800,000 deaths has been documented globally as of August 25, 2020. 1 During the course of the coronavirus disease 2019 pandemic, cardiovascular manifestations have been recognized as one of the leading complications among patients hospitalized with the disease. Elevated cardiac troponin levels or electrocardiographic changes has been reported in 7.2%-27.8% of hospitalized patients with COVID-19. [2] [3] [4] Arrhythmias have previously been described with SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) infection 5, 6 and have been reported to occur in 7%-16.7% of hospitalized patients with SARS-CoV-2 infection. 2, 3 However, data on atrial arrhythmias are limited. 7, 8 We sought to clarify the incidence of and risk factors for atrial arrhythmias among patients hospitalized with COVID-19, and to evaluate the association of atrial arrhythmias with hospital outcomes including mortality.

This retrospective observational cohort study consisted of all consecutive patients with confirmed COVID-19 who were admitted to New York-Presbyterian (NYP)/Weill Cornell Medicine (WMC), a quaternary referral center and 862-bed teaching hospital, and NYP/Lower Manhattan Hospital (LMH), a 180-bed community hospital between March 3 and April 6, 2020. This study was approved by the WMC Institutional Review Board, which waived informed consent. All cases of COVID-19 were confirmed through real-time reverse-transcriptase polymerase chain reaction assays on nasopharyngeal swabs. Using REDCap, 9 patient data were manually abstracted from NYP electronic health records to develop a COVID-19 registry as previously described. 10 The data that support the findings of this study are available from the corresponding author upon reasonable request.

Demographics (age, sex and race) and pre-existing comorbid conditions (coronary artery disease, heart failure, hypertension, diabetes, prior history of atrial fibrillation (AF), pulmonary disease, renal disease (defined as creatinine ≥2.0 mg/dl or need for hemodialysis) and active cancer were abstracted from the electronic health record.

Hypoxia on presentation was defined as use of supplemental oxygen in the emergency department within 3 h of presentation as abstracted from respiratory flowsheets. Chest radiographic findings were abstracted from the initial and any follow-up radiology reports and categorized based on the most abnormal findings.

All standard 12-lead electrocardiograms (ECGs) recorded during each hospitalization were reviewed. ECGs were recorded at 25 mm/s and 1 mV/cm according to standard protocol. ECG measurements were performed using MUSE software (GE Healthcare) including QT interval and heart rate. Hospitalization events that occurred through May 10, 2020 were determined based on review of clinical progress notes and discharge summaries. The hospital course of patients discharged but readmitted during the clinical study period was also included in the analysis. Use of antiviral medications, hydroxychloroquine, steroids, and vasopressors during hospitalization was abstracted. Laboratory values including serum troponin I (TnI), C-reactive protein (CRP), B-type natriuretic peptide (BNP), D-dimer, erythrocyte sedimentation rate (ESR), and ferritin were abstracted.

Echocardiographic data on left ventricular ejection fraction and right ventricular function were recorded. Complications including intensive care unit (ICU) admission, respiratory failure requiring mechanical ventilation, bacteremia, venous thromboembolism, arterial thromboembolism, stroke or transient ischemic attack (TIA), and acute kidney injury requiring renal replacement therapy were abstracted.

The primary outcome of the study was 30-day all-cause mortality.

Since data collection was complete through May 10, 2020, 30-day inhospital mortality data were available for all patients. The main explanatory variable was atrial arrhythmia, which was defined as AF or atrial flutter/tachycardia (AFL). Newly detected atrial arrhythmia was a secondary explanatory variable. Arrhythmias were identified by review of all ECGs performed during hospitalization and of all telemetry strips with documentation of arrhythmias in the electronic medical records. Arrhythmias were defined to be ≥30 seconds in duration and was diagnosed on the basis of ECG or telemetry strips.

ECG and telemetry findings were adjudicated by study investigators (BP, KM, XY, JK, and JWC). Disagreements on adjudication were resolved by consensus. Patients with AF or AFL who did not have a prior history of atrial arrhythmias were considered to have newly detected AF/AFL. Secondary endpoints included arterial thromboembolic, stroke or TIA events.

Categorical variables are shown as frequencies, and continuous variables are presented as mean ± SD or median (interquartile range [IQR] ) depending on normality of distribution. For comparisons of categorical variables, the χ 2 or Fisher exact tests were used. For comparisons of continuous variables, the Student t test or Wilcoxon rank-sum test were used. First, we examined predictors of AF/AFL. We created multivariable logistic regression models by including baseline demographic characteristics (age, sex, and race), co-morbid conditions (coronary artery disease, heart failure, prior history of AF/AFL, hypertension, diabetes, pulmonary disease, renal disease, immunosuppression, smoking status, and cancer), and marker of disease severity at presentation (hypoxia in emergency department) that had univariate significance (p < .10) for the explanatory variables of interest. Finally, we examined whether AF/AFL was independently associated with the primary endpoint of 30-day mortality. This was performed by creating multivariable logistic regression models by including presence of arrhythmias, baseline demographic characteristics, co-morbid conditions and disease severity at presentation that had univariate significance for the primary endpoint. Survival curves were generated using the Kaplan-Meier method and compared by using the log-rank statistic.

All analyses were performed using SAS version 9.4 (SAS Institute) and SPSS version 24 (IBM). All tests were two-sided with p < .05 indicating statistical significance. The clinical characteristics of the study patients stratified by the presence or absence of atrial arrhythmias are summarized in Table 1 .

Compared to patients without AF/AFL, patients with AF/AFL were older with a higher proportion of males and whites. Patients with AF/AFL also had significantly more co-morbidities including coronary artery disease, heart failure, prior history of AF/AFL, prior history of stroke, hypertension, pulmonary disease, and renal disease. Finally, a higher proportion of patients with AF/AFL were on medications, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers and statins. In multivariable regression analysis, age, male sex, prior history of AF, renal disease, and hypoxia on presentation were independently associated with the occurrence of AF/AFL (Table 2 ).

Compared to patients without AF/AFL, patients with AF/AFL more frequently had abnormal chest radiographs (90.3% vs. 83.6%;

F I G U R E 1 Newly detected atrial fibrillation in a patient with coronavirus disease 2019 . A 76-year-old female admitted with hypoxia and COVID-19 developed atrial fibrillation with rapid ventricular response (top strip: V 1 electrocardiogram) on hospital day 2 and was treated with amiodarone and digoxin. She then developed respiratory failure requiring mechanical ventilation. On hospital day 17, in the setting of potassium level of 2.2 mEq/ml and digoxin level of 0.62 ng/ml, she had ventricular bigeminy and torsade de pointes with prolonged QT interval (bottom strip: telemetry). Time course of treatments are shown. p = .028) ( Table 3) . Among 146 (13.9%) patients who underwent echocardiographic imaging, there were no significant differences in left ventricular ejection fraction or proportion of patients with left or right ventricular dysfunction between patients with and without AF/AFL. Myocardial injury with peak troponin I levels ≥0.5 ng/ml were seen in 26.3% of patients with AF/AFL compared to 11.1% of patients without AF/AFL (p < .001). Overall, the AF/AFL group had significantly higher peak levels of TnI, CRP, BNP, D-dimer, ESR and ferritin when compared to patients without arrhythmias (p < .001 for all) (Figure 2 ). Patients with AF/AFL were more likely to undergo treatment with hydroxychloroquine, remdesivir, steroids, IL-6 inhibitors, and intravenous gamma globulin as outlined in Table 4 .

Compared with patients without AF/AFL, patients with AF/AFL had significantly more complications during their hospital course including respiratory failure requiring mechanical ventilatory support, hypotension requiring vasopressors, bacteremia, stroke or TIA, and venous thromboembolism ( Table 4 ). Consistent with these findings, they were also more likely to be admitted to ICUs. Among patients with AF/AFL, 10 (6.0%) had documented stroke or TIA. Of these patients, two (20%) were on therapeutic anticoagulation at the time of diagnosis of the event (one patient was on direct oral anticoagulant therapy and the other patient was on subcutaneous enoxaparin). Of the remaining eight patients, four were not on any anticoagulation at the time of stroke or TIA due to concerns for active bleeding while the remaining four were on prophylaxis dosing of subcutaneous heparin or enoxaparin ( 

In this study of atrial arrhythmia identified in a multi-center cohort of over 1000 consecutive patients hospitalized with COVID-19, we identified several important findings. First, AF/AFL was seen in over 15% of patients, with greater than 60% of these occurring in patients without any prior history of AF. Second, age, male sex, prior history of AF, renal disease, and hypoxia on presentation were all independently associated with occurrences of atrial arrhythmias. Third, the presence of AF/AFL tracked with markers of disease severity, such as abnormal chest radiographs, need for ICU admission, vasopressors, mechanical venti- 

This study has implications for treatment and management of COVID-19. First, AF was the most frequent arrhythmia seen in the patients in our study. Stroke or TIA was seen in 6% of AF patients, with 80% of those events occurring while the patients were not on therapeutically dosed anticoagulation. In the context of the high 

This is a retrospective study with data obtained via chart abstraction and review, which may be subject to error or interpretation.

However, the process utilized in this study has previously shown excellent reliability (mean Cohen's kappa, 0.92; mean intraclass coefficient, 0.94). 10 Abbreviations: AFL, atrial flutter/tachycardia; CI, confidence interval; OR, odds ratio.

Charalambia Louka

Goyal is supported by American Heart Association grants 18IPA34170185 and 20CDA35310455. This study received support from NewYork-Presbyterian Hospital (NYPH) and Weill Cornell Medical College (WCMC), including the Clinical and Translational Science Center (CTSC) (UL1 TR000457) and Joint Clinical Trials Office (JCTO)

Cheung has received consulting fees from Abbott

Safford has received research grant support from Amgen. The other authors report no relevant disclosures

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