key: cord-0962794-mowd4k7e
authors: Garcia‐Zamora, Sebastian; Lee, Sharen; Haseeb, Sohaib; Bazoukis, George; Tse, Gary; Alvarez‐Garcia, Jesus; Gul, Enes Elvin; Çinier, Göksel; Alexander, Bryce; Martins Pinto‐Filho, Marcelo; Liu, Tong; Baranchuk, Adrian
title: Arrhythmias and electrocardiographic findings in Coronavirus disease 2019: A systematic review and meta‐analysis
date: 2021-05-18
journal: Pacing Clin Electrophysiol
DOI: 10.1111/pace.14247
sha: 06965161c02542fbb974c85e0f49d632af9b8b80
doc_id: 962794
cord_uid: mowd4k7e

BACKGROUND: Coronavirus disease 2019 (COVID‐19) primarily causes lung infection, but recent studies have shown that cardiac involvement is associated with a worse prognosis. OBJECTIVES: We conducted a systematic review and meta‐analysis to examine the prevalence of cardiac arrhythmias detected by the electrocardiogram and their relationships with adverse outcomes in patients with COVID‐19. METHODS: PubMed and Google were searched for studies that reported on cardiac arrhythmias and/or examined the relationship between arrhythmias and adverse outcomes. RESULTS: Thirty studies with 12,713 participants were included in the systematic review, and 28 studies (n = 12,499) in the meta‐analysis. The mean age was 61.3 ± 16.8 years; 39.3% were female. In 25 studies with 7578 patients, the overall prevalence of cardiac arrhythmias was 10.3% (95% confidence interval [CI]: 8.4%–12.3%). The most common arrhythmias documented during hospitalization were supraventricular arrhythmias (6.2%, 95% CI: 4.4%–8.1%) followed by ventricular arrhythmias (2.5%, 95% CI: 1.8%–3.1%). The incidence of cardiac arrhythmias was higher among critically ill patients (relative risk [RR]: 12.1, 95% CI: 8.5–17.3) and among non‐survivors (RR: 3.8, 95%, CI: 1.7–8.7). Eight studies reported changes in the QT interval. The prevalence of QTc > 500 ms was 12.3% (95% CI: 6.9%–17.8%). ST‐segment deviation was reported in eight studies, with a pooled estimate of 8.7% (95% CI: 7.3% to 10.0%). CONCLUSION: Our meta‐analysis showed that QTc prolongation, ST‐segment deviation, and various other cardiac arrhythmias were observed in patients hospitalized with COVID‐19. The presence of cardiac arrhythmias was associated with a worse prognosis.

with COVID-19, 3, 4 and this presence has been associated with a worse prognosis. 5, 6 The surface electrocardiogram (ECG) is one of the leading tools to assess potential cardiac involvement in hospitalized patients with COVID-19. 4 Existing data shows that cardiac arrhythmias area common complication of a COVID-19 infection, although their association with adverse outcomes remains to be fully defined. 7 The aim of our systematic review and meta-analysis was to estimate the prevalence of ECG abnormalities and cardiac arrhythmias in hospitalized patients with COVID-19 and to further evaluate the association of arrhythmias with patient outcomes.

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. 8 The protocol was registered in the PROSPERO database of systematic reviews (registration number: CRD42020184448). PubMed was searched for studies that reported the prevalence of cardiac arrhythmias detected by the ECG and/or reported the relationship between cardiac arrhythmias and adverse outcomes in COVID-19. The search was performed from database inception to August 30, 2020 without language restrictions. Search terms used were: "COVID" AND ("electrocardiogram" OR "ECG" OR "QT" OR "fibrillation" OR "arrhythm*" OR "LBBB" OR "RBBB" OR "bundle branch block" OR "QRS"). Gray literature and bibliographies of included studies were also searched to extend the search cover-age. The exclusion criteria were: case reports, case series, reviews, preclinical studies, and preprints publications. Once duplicates were removed, two reviewers (YL and SGZ) independently screened titles and abstracts to ensure the capture of all relevant studies. Disagreements were resolved by discussion to achieve consensus.

Data were extracted into predetermined tables using a standardized Two reviewers (GB and GT) independently completed a risk of bias assessment using the Newcastle-Ottawa scale (NOS). 9 The NOS point scoring scale uses a star system in which each study is judged based on three domains: selection of the study groups (four items); comparability of the groups (one item); and exposure (ascertainment of the outcome; three items). A study can be awarded a maximum of one star for each numbered item within the selection and exposure categories, and a maximum of two stars for comparability.

We performed this meta-analysis based on published data, and there were no patients or public involvement in this project.

For the outcomes of interest, mean differences with 95% confidence interval (CI) were extracted and subsequently pooled. 10 If the standard error (SE) or 95% CIs were not reported, calculations were made using the following formula:

where "n" is the sample size.

Heterogeneity across studies was determined using the variance between the studies (Tau-square, τš) and the Iš statistic. The Iš statistic, determined from the standard chi-square test, describes the total variance explained by heterogeneity rather than chance. I 2 > 50% was considered to reflect significant statistical heterogeneity. If I 2 < 50%, a fixed effects model was used; otherwise, the random-effects model using the inverse variance heterogeneity method was used. [11] [12] [13] To identify the source of the heterogeneity, sensitivity analysis using the leave-one-out method was used. To assess for possible publication bias, funnel plots, Begg's, and Egger's test were used. 14 Data analysis was performed using Review Manager (RevMan) (Version 5.3) and Stata (Version 13.0).

The search identified 488 records. After the removal of duplicates (n = 37), 451 records were screened based on titles and abstracts.

Of these, 316 records were excluded because they were editorials, position papers from scientific societies, or reviews. Subsequently, full texts of 135 articles were reviewed. Of these, 102 articles were non related to the topic of interest; three articles were excluded because the ECG data were out of the scope of this review [15] [16] [17] ; Pavri et al. 15 were excluded because they evaluated the PR interval in hospitalized patients with COVID-19; Shi et al. 16 were excluded because they described the frequencies of patients with abnormal ECG findings but did not further delineate the abnormalities observed; and Lei et al. 17 were excluded because they included all patients who underwent elective surgeries, but the diagnosis of COVID-19 was made after the procedure. Finally, 30 studies were included in the qualitative review (Figure 1 ). Of these, 19 studies reported relevant ECG and/or arrhythmia findings. [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] The other 11 studies only specified cardiac arrhythmias in general without further elaboration. [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] For the meta-analysis, two studies (from the 30 included studies) were excluded as they only provided qualitative data on QT intervals. 30, 32 The quality assessment of the included studies are summarized in Table S1 .

We included 30 studies with 12,713 participants. The sample size varied from 16 to 5700 patients (median: 128 patients, interquartile range: 90-380). The mean age was 61.3 ± 16.7 years, and 42.0% were female. All of the included studies were cohort studies, with the exception of Borba et al. 20 who reported the findings of a randomized con-

What is already known about this subject? and China (n = 11). All but one study 34 included adult patients, with most participants over 40 years of age. Samuel et al. 34 included pediatric and adolescent patients, with a mean age of 13 ± 6 years.

All studies reported medical comorbidities. The most common was hypertension (45%), followed by obesity (34%), and diabetes mellitus (24%). Obesity was most commonly reported among patients from the United States. 18, 19, 25, [27] [28] [29] 32, 33, 37, [41] [42] [43] Overall, 11% of the patients had coronary artery disease. There were variations in the mortality rates amongst the studies (12% ± 2%, range: 0%-27.2%). There were variations in the disease severity of COVID-19-ranging from stable to severe or critical patients requiring mechanical ventilation or cardiac support-and differences in the treatments offered (Tables 1 and 2 ).

In our meta-analysis of 28 studies, 18 25 studies (n = 7578), though there was substantial heterogeneity between the studies (I 2 = 100%) ( Figure 1A ). Sensitivity analysis, excluding data from pediatric and adolescent patients, did not significantly alter the overall frequency of arrhythmias (10%, 95% CI:

8.1%-12%) ( Figure S1 ).

Specific types of arrhythmias were reported by 15 studies (Table 3) .

The most common was supraventricular tachyarrhythmias (n = 3395 from nine studies, 6.2%, 95% CI: 4.4%-8.1%; I 2 = 100%) (Figure 1B) , 18, 19, 21, 23, 25, 28, [33] [34] [35] followed by ventricular tachyarrhythmias (n = 3485 from 11 studies, 2.5%, 95% CI: 1.8%-3.1%; I 2 = 100%) (Figure 1C) . [19] [20] [21] [22] [25] [26] [27] 29, [34] [35] [36] Bradyarrhythmias were the least common (n = 1560 from four studies, 1.8%, 95% CI: 1.0%-2.5%; I 2 = 100%) (Figure S2) . 18, 19, 21, 28 

Changes in the QT interval during COVID-19 hospitalization were reported by 16 studies (Table 4) . 18, 20, 22, [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [41] [42] [43] The most frequent criteria to define substantial QTc prolongation was QTc duration > 500 ms when the QRS duration was < 120 ms and QTc > 550 ms when the QRS duration was ≥120 ms. Due to disparities in the reported data, only six studies (n = 4812) were included in our meta-analysis for QT prolongation. 18, 20, 22, 29, 31, 42 The overall prevalence of QTc > 500 ms was 12.3% (95% CI: 6.9%-17.8%; I 2 = 100%) (Figure 2A) .

The presence or absence of ST-segment deviation was reported in eight studies (n = 1598) with a pooled estimate of 8.7% (95% CI: 7.35%-10.0%; I 2 = 100%) ( Figure 2B) . 18, 21, 23, 24, 27, 34, 37 

Eight studies reported the relationship between new-onset cardiac arrhythmias and adverse outcomes in patients with COVID-19 (n = 2112, 56.1 ± 17.8 years, 46.4% female). 19, 21, 23, 25, 36, 44, 46, 47 Regarding the definition of disease severity, Bhatla et al., 19 Colon et al., 23 Yenercag et al., 36 Wang et al., 44 ( Figure S4 ).

The relationship between cardiac arrhythmias and inpatient mortality was only reported by three studies (n = 1197, 62 ± 16 years old, 45.0% female). 28, 36, 45 Non-survivors were more likely to develop cardiac arrhythmias compared to survivors during their inpatient stay (RR: 3.8, 95% CI: 1.7-8.7; I 2 = 76%) ( Figure 2D ). Of these three studies, only one reported the specific type of arrhythmias observed, which was supraventricular arrhythmias observed in all patients. 28 In this study, non-survivors were also found to be at a higher risk of developing supraventricular arrhythmias (RR: 2.3, 95% CI: 1.2-4.5) ( Figure S5 ).

In Figure 4 , we have summarized the main findings our study relating to cardiac arrhythmias and ECG abnormalities among hospitalized COVID-19.

Regarding potential publication bias between analyzed studies, a visual inspection of funnel plots suggested an asymmetric distribution of the occurrence of cardiac arrhythmias in hospitalized COVID-19 patients ( Figure S6 ). The Begg's test suggested no significant publication bias (z = 1.38; p = .17). The Egger test demonstrated significant asymmetry (t-value −3.0; p = .006) ( Figure S7 ). Sensitivity analysis, excluding one study at a time (leave-one-out method), did not reduce the heterogeneity of the results.

The main findings of this systematic review and meta-analysis are: (i) cardiac arrhythmias are a common complication among hospitalized COVID-19 patients, and (ii) cardiac arrhythmias can be considered a marker of worsening prognosis.

To the best of our knowledge, this is the largest meta-analysis reporting on the prevalence of ECG findings in hospitalized COVID-19

patients. We found that the frequency of cardiac arrhythmias showed a wide range across the studies, which could be attributable to the differences in the patients' comorbidities and variations seen across disease severity and treatments offered. In our study, premature beats were excluded in order to avoid an overestimation of the clinically significant arrhythmias. Among specific arrhythmias reported across the studies, supraventricular arrhythmias were the most frequent, followed by ventricular arrhythmias. In contrast, bradyarrhythmias were the least observed arrhythmias. Furthermore, the risk of cardiac arrhythmias was higher among non-survivors and critically ill patients hospitalized with COVID-19.

ST-segment changes were the most frequently reported ECG finding. This is a significant ECG abnormality caused by different pathologies such as pericarditis, Takotsubo cardiomyopathy, and acute coronary syndrome. Additionally, QTc prolongation is a significant concern during COVID-19 infection and could be largely attributable to drugs that cause delayed repolarization. 3 However, we were unable to fully evaluate the prognostic implications of ST-segment changes and QT prolongation due to the significant disparities in the reported data across the studies.

Cardiac involvement in COVID-19 has a wide spectrum, and contemporary high sensitivity troponin tests might be elevated in critically ill patients even without apparent myocardial involvement. 48, 49 Nevertheless, previous studies have linked cardiac involvement with a worse prognosis in COVID-19. 50 ECG abnormalities are intrinsically related to cardiac pathology, and our findings are in agreement with these observations.

Our study has important limitations. Firstly, about half of the included articles did not report the types of arrhythmias observed. We were, therefore, unable to accurately estimate the incidence and prevalence of electrocardiographic abnormalities in hospitalized patients with COVID-19. Secondly, we could not investigate the relationship between specific types of arrhythmias and the severity of COVID-19 infection. This information was not consistently reported across the included studies, likely because most studies did not examine cardiac arrhythmias as a specific risk factor for adverse outcomes.

Finally, we found high heterogeneity for most comparisons except for the occurrence of arrhythmias in critically ill patients. Nevertheless, such heterogeneity could have a clinical origin due to the differences in the study cohorts amongst the included studies.

Our systematic review and meta-analysis showed that QTc prolongation, ST-segment deviation, and other forms of cardiac arrhythmias were observed in patients hospitalized with COVID-19. The presence of cardiac arrhythmias was associated with a worse prognosis. Future studies are needed to explore the possible role of arrhythmias in relation to patient outcomes.

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SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article

Arrhythmias and Electrocardiographic findings in Coronavirus disease 2019: a systematic review and meta-analysis

The present systematic review and meta-analysis has not received any grants or financial support.

Nothing to declare.

Our meta-analysis was based on published data and did not require approval from an Ethical committee. Baranchuk.

The data that support the findings of this systematic review and metaanalysis are available in the studies listed in references.