Electrocardiography on admission is associated with poor outcomes in coronavirus disease 2019 (COVID‐19) patients: A systematic review and meta‐analysis

Abstract Background Electrocardiogram (ECG) is a widely accessible diagnostic tool that can easily be obtained on admission and can reduce excessive contact with coronavirus disease 2019 (COVID‐19) patients. A systematic review and meta‐analysis were performed to evaluate the latest evidence on the association of ECG on admission and the poor outcomes in COVID‐19. Methods A literature search was conducted on online databases for observational studies evaluating ECG parameters and composite poor outcomes comprising ICU admission, severe illness, and mortality in COVID‐19 patients. Results A total of 2,539 patients from seven studies were included in this analysis. Pooled analysis showed that a longer corrected QT (QTc) interval and more frequent prolonged QTc interval were associated with composite poor outcome ([WMD 6.04 [2.62‐9.45], P = .001; I 2:0%] and [RR 1.89 [1.52‐2.36], P < .001; I 2:17%], respectively). Patients with poor outcome had a longer QRS duration and a faster heart rate compared with patients with good outcome ([WMD 2.03 [0.20‐3.87], P = .030; I 2:46.1%] and [WMD 5.96 [0.96‐10.95], P = .019; I 2:55.9%], respectively). The incidence of left bundle branch block (LBBB), premature atrial contraction (PAC), and premature ventricular contraction (PVC) were higher in patients with poor outcome ([RR 2.55 [1.19‐5.47], P = .016; I 2:65.9%]; [RR 1.94 [1.32‐2.86], P = .001; I 2:62.8%]; and [RR 1.84 [1.075‐3.17], P = .026; I 2:70.6%], respectively). T‐wave inversion and ST‐depression were more frequent in patients with poor outcome ([RR 1.68 [1.31‐2.15], P < .001; I 2:14.3%] and [RR 1.61 [1.31‐2.00], P < .001; I 2:49.5%], respectively). Conclusion Most ECG abnormalities on admission are significantly associated with an increased composite poor outcome in patients with COVID‐19.


| INTRODUC TI ON
On January 30, 2020, the World Health Organization (WHO) declared 2019 coronavirus disease , an infectious disease caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), as a pandemic. 1 As of November 22, 2020, it was reported that more than 57.8 million people worldwide were infected with COVID-19, causing more than 1.3 million fatalities. 2 While most of the focus is on diseases and complications of the lung, one cannot ignore myocardial injury as it can worsen the prognosis and increase mortality. 3,4 SARS-CoV-2 binds to the host cell surface via the angiotensin-converting enzyme 2 (ACE2) receptor, which causes pulmonary infection and cardiac complications of acute myocardial injury (27.8%) and arrhythmias (44.4%). [5][6][7] Due to the severe complications in the heart, a diagnostic tool is needed to help predict the condition of the patients quickly during admission. Electrocardiography (ECG) is a widely available diagnostic tool that can be done immediately and can reduce excessive contact with the patient. Previous studies have reported that many COVID-19 patients present with ECG alterations associated with cardiac involvement, such as a prolonged QTc interval, ST-segment abnormalities, atrial and ventricular arrhythmias, and conduction block. 8,9 Therefore, we performed a systematic review and metaanalysis to evaluate the latest evidence on the association of ECG on admission and the poor outcomes in COVID-19.

| Eligibility criteria
We included all studies evaluating ECG parameters on admission and outcomes comprising ICU admission, severe illness, and mortality in patients who tested positive for SARS-CoV-2 using the reverse transcription-polymerase chain reaction (RT-PCR) test. Unpublished studies, animal or in-vitro studies, review articles, case reports, non-English articles, and studies with irrelevant or non-extractable results were excluded from the analysis.

| Search strategy and study selection
We conducted a systematic literature search for January 1, 2020, to November 1, 2020, from PubMed, the Cochrane Library Database, and Europe PMC using the search strategy shown in Table S1. After the initial search, duplicate articles were removed.
The abstracts and titles of the remaining articles were screened by two authors (MJA and YA) independently. Subsequently, the relevant articles in the full text were assessed based on the eligibility criteria. Disagreements were resolved by conferring with the senior writer (MYA). This research was conducted following the Preferred Reporting Item for Systematic Reviews and Meta-Analysis (PRISMA) statement.

| Data collection process
Two authors (MJA and YA) conducted data extraction independently using standardized form extraction consisting of the author, date of publication, study design, number and characteristics of samples, ECG parameters, ICU admission, severe illness, and mortality. The ECG parameters included corrected QT (QTc) interval, prolonged QTc interval, QRS duration, PR interval, heart rate, right bundle branch block (RBBB), left bundle branch block (LBBB), premature atrial contraction (PAC), premature ventricular contraction (PVC), T-wave inversion, ST-depression, and ST-elevation. The Bazett formula (QTc = QT/(√RR)) was used to calculate the QTc interval. 10 The outcome of interest was composite poor outcomes, including ICU admission, severe illness, and mortality. The severity of the disease was defined in the diagnosis and treatment guidelines of adults with community-acquired pneumonia. 11 We used mean ± standard deviation (SD) and frequency (percentage) to present the distribution of the categorical and continuous variables, respectively.

| Quality assessment
The risk of bias and the quality of included studies were assessed using the Newcastle-Ottawa score (NOS) 12 by all authors independently, and discrepancies were resolved through discussion. This scoring system consists of three domains: sample selection, comparability of cohorts, and outcomes assessment (Table S2).

| Data analysis
Stata software V.14.0 (College Station) was used for meta-analysis.
Pooled effect estimates of the continuous and dichotomous variables were reported as weighted means differences (WMD) and relative risk (RR), respectively. We used the fixed-effects models for pooled analysis with low heterogeneity (I 2 statistic <50% or P-value >.1), while the random-effects models were used for pooled analysis with high heterogeneity (I 2 statistic >50% or P-value ≤.1). For other analyses, P-value <.05 was determined as statistical significance.
Subgroup analysis was performed for the parameter of the QTc interval. The publication bias was evaluated qualitatively using funnelplot analysis. To evaluate the small-study effects on dichotomous and continuous variables, we used the regression-based Harbord test and Egger test, respectively.

| Study characteristics
We identified 775 articles from the initial search, and 674 articles remained after the duplication was removed. Screening on titles and abstracts excluded 661 articles, and the remaining 18 full-text articles were assessed according to eligibility criteria. As a result, seven studies [13][14][15][16][17][18][19] with a total of 2,539 patients were subjected to qualitative analysis and meta-analysis ( Figure 1; Table 1). Quality assessment with NOS showed that included studies were of good quality (Table S1).

| Electrocardiogram parameters and outcome
Meta-analysis showed that longer QTc interval was found in patients with poor outcome (weighted means difference, WMD 6.04 [2.62-9.45], P = .001; I 2 :0%) compared with patients with good outcome.
Prolonged QTc interval was associated with composite poor outcome (relative risks, RR 1.89 [1.52-2.36], P < .001; I 2 :17%  Figure 2). Other ECG parameters such as PR interval and incidence of RBBB and ST-elevation were not significantly associated with poor outcomes ( Figure S1).

| Publication bias
The visual assessment of the funnel plot showed an asymmetrical shape for the analysis of the QTc interval, which indicated the possibility of publication bias ( Figure 3). However, quantitative analysis using regression-based Egger's test for the same variable showed no significant result of small-study effects (P = .262).
Regression-based Harbord's test for other ECG parameters and composite poor outcome also showed no significant result of small-study effects.

| D ISCUSS I ON
Cardiac injury is one of the complications that represent severe COVID-19, 3 and the ECG is still the simplest tool to assess myocardial involvement. This meta-analysis revealed that, on admission ECG, pa- sulting in after early after depolarizations (EADs) and delayed after depolarizations (DADs), which will be discussed in more depth later.
The QT interval is the ventricular period of depolarization and repolarization, depicted from the beginning of the Q wave to the end of the T wave. 22 Abnormal prolongation of this period can cause lifethreatening ventricular arrhythmias, especially torsade de pointes (TdP). 23 Preexisting prolonged QTc (>500 ms) is prevalent in patients with COVID-19. In New York City hospital, prolonged QTc was found on 260 of 4250 patients (6.1%) at admission. 24 Another study reported that nearly 10% of 623 COVID-19 patients were admitted with a prolonged QTc interval (QTc >480 ms), and prolonged QTc was significantly associated with higher fatality rates. 25 The present meta-analysis showed that COVID-19 patients with preexisting prolonged QTc tend to have poor outcomes.
Many factors contribute to a prolonged QTc interval in the patient with COVID-19, but it is likely due to the inflammation and COVID-19 patients experienced increased heart rate as the most common finding of rhythm disturbances on hospital admission. 36,37 The increased heart rate also the most common ECG abnormalities in the patient with SARS, with the incidence of around 72%. 38 The present meta-analysis showed that COVID-19 patients with increased heart rate tend to have a poor outcome. Consistent with this finding, a previous study showed that COVID-19 patients who need to be treated in the ICU have a faster heart rate compared with the general ward. 37 A study related to COVID-19 mortality also showed that non-survivor have significantly faster baseline heart rates on admission compared with survivors. 39 The

F I G U R E 3
Funnel-plot analysis. WMD, weighted mean differences increased heart rate might be related to the increased risk of atrial tachyarrhythmias, which were common in COVID-19 patients admitted to the ICU and often followed by hemodynamic deterioration, thus leading to poor outcomes. 4 The mechanisms that underlie atrial tachyarrhythmias and tachycardia in these patients may be due to systemic infection, direct viral cardiomyocyte injury, hypoxia, and natural susceptibility of aged, comorbid-laden individuals. 40 Hypoxia has been shown to directly cause tachycardia in human studies involving spectral analysis of R-to-R interval series. Hypoxia was shown to attenuate autonomic nervous system activities with the sympathovagal balance leaning more heavily toward sympathetic dominance. 41 The present meta-analysis showed that COVID-19 patients with longer QRS duration and incidence of LBBB tend to have poor outcomes. In COVID-19 patients, longer QRS duration and the presence of LBBB may indicate intraventricular conduction delay, which can be a sign of myocardial injury and led to pump failure, which is independently associated with death. 14,17 Similarly, patients with myocarditis with a prolonged QRS complex was associated with lower left ventricular function and higher cardiovascular mortality. 42 The present study also showed that the presence of PAC and PVC on admission ECG was more frequent in COVID-19 patients with poor outcomes. As previously explained, infection of SARS-COV2 triggers overexpression of AngII, which subsequently causes dysfunctional CAMCK-II activity downstream and eventually PAC and PVCs. [25][26][27][28][29][30] Besides this, the appearance of PAC may also be caused by transient systolic and diastolic dysfunction due to cytokine hypersecretion in COVID-19 patients. 43 The presence of a PAC detected on baseline ECG recording was associated with an increased risk of developing AF, which could increase the risk of congestive heart failure, ischemic heart disease, and sudden cardiac death. 43,44 Aside from that, the presence of PVC has been detected in 4.4% up to 5% of COVID-19 patients undergoing standard 12-leads ECG on admission. 13,15 The inflammatory process in COVID-19 is also considered to play a role in the incidence of PVC. A retrospective study of 264 patients undergoing ambulatory Holter ECG monitoring showed that the neutrophil-lymphocyte ratio (NLR) was found higher in the PVC group and was independently associated with the presence of PVC, suggesting the role of the inflammatory cytokine storm. 45 The PVC existence may also represent an underlying disease that indirectly explains the role of PVC in increasing poor outcomes in COVID-19 patients through the involvement of heart failure. A cohort study conducted by Atherosclerosis Risk in Communities (ARIC) shows that PVC is associated with the prevalence of heart failure. 46 Other than these mechanisms, PVC will eventually increase the risk of more malignant dysrhythmias such as sustained VT or VF, which leads to sudden cardiac death. 47 Another ECG manifestation of cardiac involvement in rates. 54 Since both higher heart rates and prolonged QTc intervals are significantly associated with increased poor outcomes in COVID-19 patients, the effect of prolonged QTc intervals in poor outcomes may be exaggerated by Bazett's formula overcorrecting the QT interval.

| CON CLUS ION
This meta-analysis showed ECG abnormalities on admission, including longer QTc interval and prolonged QTc interval, longer QRS duration, a faster heart rate, the presence of LBBB, PAC, PVC, T-wave inversion, and ST-depression are significantly associated with an increased composite poor outcome in patients with COVID-19.

| CLINIC AL IMPLIC ATION
• Several ECG abnormalities on admission (longer QTc interval, prolonged QTc interval, longer QRS duration, faster heart rate, LBBB, PAC, PVC, T-wave inversion, and ST-depression) are associated with poor outcome in COVID-19 patients.
• Risk stratification of COVID-19 patients must be done early, and admission ECG can be used to identify the underlying disease.
• In patients with prolonged QTc intervals at the baseline and patients with inherited arrhythmic syndromes, ECG should be evaluated and monitored regularly.

CONFLI C TING OF INTERE S TS
The authors declare no conflict of interest for this article.

E TH I C S A PPROVA L
Not applicable.