Risks of Cardiac Arrhythmia Associated with COVID-19 Vaccination: A Systematic Review and Meta-Analysis

This systematic review and meta-analysis aimed to summarize the current evidence regarding the association between coronavirus disease 2019 (COVID-19) vaccination and the risk of cardiac arrhythmia. MEDLINE, via PubMed and OVID, Scopus, CENTRAL, and Web of Science were searched using the relevant keywords to identify the relevant citations. Comprehensive Meta-analysis and Review Manager 5.4.1 were used for all the statistical analyses. Seventeen studies (n = 567,033,087 patients) were included. The pooled analysis showed that the incidence of cardiac arrhythmia post-COVID-19 vaccination with Pfizer, Moderna, AstraZeneca, CoronaVac, and Sinopharm was 0.22%, 95% CI: (0.07% to 0.66%), 0.76%, 95% CI: (0.04% to 12.08%), 0.04%, 95% CI: (0.00% to 0.98%), 0.01%, 95% CI: (0.00% to 0.03%), and 0.03%, 95% CI: (0.00% to 18.48%), respectively. Compared to CoronaVac, Pfizer, Moderna, AstraZeneca, and Sinopharm had a higher incidence ratio rate (IRR; 22-times, 76-times, 4-times, and 3-times higher), respectively. Likewise, Pfizer, Moderna, and AstraZeneca showed a higher IRR than Sinopharm (7.3-times, 25.3-times, and 1.3-times higher). The current evidence shows that the incidence rate (IR) of cardiac arrhythmia post-COVID-19 vaccination is rare and ranges between 1 and 76 per 10,000. mRNA vaccines were associated with a higher IR of arrhythmia compared to vector-based vaccines. Inactivated vaccines showed the lowest IR of arrhythmia.


Introduction
Different treatment options have been investigated since the inception of the coronavirus disease 2019 (COVID-19) pandemic in late 2019, including immunotherapy, nucleoside analogs, and others [1,2]. To prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or to lessen the severity of the disease, with the ultimate aim of reducing mortality and morbidity, researchers have investigated a variety of platforms for vaccine development, including protein-based and viral-based vaccines [3,4].
There were 128 vaccines under clinical development as of 22 October 2021, with another 194 in the pre-clinical stage [5]. B-cell response, helper T cells, and cytotoxic cells are prompted by COVID-19 mRNA vaccines such as BNT1626b2 (i.e., Pfizer/BioNTech vaccine) and mRNA1273 (i.e., Moderna vaccine) [6]. Regarding vector vaccination, the COVID-19 virus's genetic material is inserted into a modified form of another virus, which facilitates the delivery of genetic material from the COVID-19 virus that induces copies of the S protein [7]. The production of antibodies and protective white blood cells is triggered once S proteins are presented on the surface of the body cells. The Johnson & Johnson (Ad26.COV2.S) and Oxford and AstraZeneca (ChAdOx1) COVID-19 vaccines are vectors [8]. Protein subunit vaccines use fragments of protein from the disease-causing virus to trigger protective immunity against it. Studies have revealed that these protein vaccines include S proteins that are not pathogenic. Once the S proteins are recognized by the immune system, antibodies and protective white blood cells are generated [9]. The Novavax COVID-19 vaccine (NVX-CoV2373) is one of these protein-based vaccines. Since the approval of these vaccines, regardless of their type, several reports worldwide have emerged, documenting various adverse events, including local and systemic reactions.
Myalgia, headache, fever, edema, erythema, and pain at the injection site were the most common local or systemic reactions observed [10][11][12]. However, a number of serious and potentially fatal adverse events and complications have been documented in association with COVID-19 vaccinations, including venous thromboembolism, stroke, pulmonary embolism, cardiac arrhythmias, and myocardial infarction [13][14][15]. The unfavorable cardiac outcomes linked to COVID-19 vaccinations can range from inflammations (such as pericarditis or myocarditis) to thrombosis and ischemia [15,16]. Several systematic reviews and meta-analyses have investigated the risk of myocarditis/pericarditis, thrombocytopenia, and thrombosis in vaccinated COVID-19 individuals [17][18][19][20][21]. However, to the best of our knowledge, there is no large-scale study or meta-analysis that investigates the association between COVID-19 vaccination and cardiac arrhythmia. Therefore, in this systematic review and meta-analysis, we aimed to summarize the current evidence regarding the association between COVID-19 vaccination and the risk of arrhythmia.

Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and Cochrane handbook for systematic reviews of interventions were followed in the reporting of this study [22,23]. The study protocol (CRD42022371085) was registered on PROSPERO.

Eligibility Criteria
The studies were included based on the following criteria: Population: studies that were conducted on the individuals who received any type or dose of the COVID-19 vaccine.
Outcomes: studies reported cardiac arrhythmia as an adverse event of one of the aforementioned vaccines.
Studies design: observational studies (case-control, cohort, and cross-sectional). We excluded case reports, conference abstracts, and non-English studies.

Selection Process
Using Microsoft Excel software, a screening sheet was created. Study ID, publication year, title, abstract, keywords, DOI, and URL were all included. The selection process was undertaken using a two-step screening technique by three independent reviewers (B.I.A, R.O.A, and B.D.A).
Step one included screening the title and abstract of all the studies found via the literature search to determine which studies might proceed to step two (full-text screening), where reviewers would read and assess whether each study met the eligibility criteria. Any disagreement between the reviewers was resolved by the judgment of the study supervisor (M.A).

Data Items and Collection Process
Four independent reviewers extracted the following data from the included studies to an offline pre-prepared Excel sheet: demographic data of the included patients (age, gender, and residency), study characteristics (study groups, study duration, total sample size, country, and main findings) and outcomes (incidence rate of arrhythmia following COVID-19 vaccination).

Risk of Bias and Quality Assessment
Using the National Institutes of Health (NIH) quality assessment tool for observational cohort, case-control, and cross-sectional studies, two authors (A.M.N and A.A.A) independently evaluated the risk of bias and the quality of each included article. Reviewers can critically evaluate the internal validity of research using this tool. Studies were deemed to be "good," "fair," or "poor". When the authors disagreed on a rating, a third author (M.A) resolved any disagreements.

Data Synthesis
The incidence of adverse events was calculated using the random-effects model with a 95% CI. Using the I 2 statistic, we calculated the percentage of heterogeneity and inconsistency between studies, with values of 25%, 50%, and 75% deemed as low, moderate, and high, respectively. The random-effect model was employed if the heterogeneity was considerable and if I 2 > 50%; otherwise, the fixed-effect model was utilized. Comprehensive Meta-analysis software was used for all the statistical analyses (Biostat, Inc., CMA; USA: version 3.3.070, Florida, 33618, United States). To assess the difference between Pfizer-BioNTech and AstraZeneca in terms of AEs, we used the Review Manager 5.4 software to calculate the risk ratio (RR) between both groups using the Mantel-Hansel model.

Characteristics of Included Studies and Patients
Three studies were cohort studies, three were cross-sectional, eight were retrospective studies, two were controlled case-series studies, and one was a subgroup analysis study. Four studies were multicentric studies, three were from the USA, three were from Israel, one was from Malaysia, one was from Saudi Arabia, one was from Singapore, one was from Turkey, one was from India, one was from China, and one was from England. The Pfizer-BioNTech vaccine was reported in 12 studies, AstraZeneca in 3, CoronaVac in 3, and Moderna in 7. The age of the included patients ranged between 12 and 90 years old. Both males and females were represented in the included studies. Table 1 summarizes the baseline characteristics of the included studies and patients.

Characteristics of Included Studies and Patients
Three studies were cohort studies, three were cross-sectional, eight were retrospective studies, two were controlled case-series studies, and one was a subgroup analysis study. Four studies were multicentric studies, three were from the USA, three were from Israel, one was from Malaysia, one was from Saudi Arabia, one was from Singapore, one was from Turkey, one was from India, one was from China, and one was from England. The Pfizer-BioNTech vaccine was reported in 12 studies, AstraZeneca in 3, CoronaVac in 3, and Moderna in 7. The age of the included patients ranged between 12 and 90 years old. Both males and females were represented in the included studies. Table 1 summarizes the baseline characteristics of the included studies and patients.

Quality of the Included Studies
Based on the NIH quality assessment tool for observational studies, about 88.2% of the studies were deemed as "Good," and 11.8% were deemed as "Fair".

Incidence of Cardiac Arrhythmia
The pooled analysis of 12 studies showed that the incidence of cardiac arrhythmia post-Pfizer COVID-19 vaccine was 0.22%, 95% CI: (0.07% to 0.66%), which means that the incidence rate was 22 per 10,000 persons ( Table 2). The random-effect estimate of four studies demonstrated that the pooled incidence of arrhythmia post-Moderna COVID-19 vaccine was 0.76%, 95% CI: (0.04% to 12.08%). Compared to Pfizer, the Moderna vaccine had an incidence rate ratio (IRR) of 3.45, meaning that the group that received the Moderna vaccine had a 3.45-times higher risk of developing cardiac arrhythmia than Pfizer. This finding was supported by the lower RR of cardiac arrhythmia associated with the Pfizer vaccine compared to the Moderna vaccine; however, the difference was not statistically significant (RR = 0.60, 95% CI: 0.28 to 1.29; Figure 2).   The pooled analysis of three studies showed that the incidence of arrhythmia post-AstraZeneca vaccine was 0.04%, 95% CI: (0.00% to 0.98%). The IRR arrhythmia post-Pfizer or Moderna COVID-19 vaccines was 5.5-times and 19-times higher than the IRR of arrhythmia post-AstraZeneca vaccine. Similarly, the pooled RR showed that the Pfizer vaccine had a non-significantly higher RR compared to AstraZeneca (RR = 1.63, 95% CI: 0.77 to 3.46; Figure 3). On the other hand, AstraZeneca and Moderna had a comparable RR (1.28, 95% CI: 0.03 to 48.96; Figure 4).  The pooled analysis of three studies showed that the incidence of arrhythmia post-AstraZeneca vaccine was 0.04%, 95% CI: (0.00% to 0.98%). The IRR arrhythmia post-Pfizer or Moderna COVID-19 vaccines was 5.5-times and 19-times higher than the IRR of arrhythmia post-AstraZeneca vaccine. Similarly, the pooled RR showed that the Pfizer vaccine had a non-significantly higher RR compared to AstraZeneca (RR = 1.63, 95% CI: 0.77 to 3.46; Figure 3). On the other hand, AstraZeneca and Moderna had a comparable RR (1.28, 95% CI: 0.03 to 48.96; Figure 4). The pooled analysis of three studies showed that the incidence of arrhythmia post-AstraZeneca vaccine was 0.04%, 95% CI: (0.00% to 0.98%). The IRR arrhythmia post-Pfizer or Moderna COVID-19 vaccines was 5.5-times and 19-times higher than the IRR of arrhythmia post-AstraZeneca vaccine. Similarly, the pooled RR showed that the Pfizer vaccine had a non-significantly higher RR compared to AstraZeneca (RR = 1.63, 95% CI: 0.77 to 3.46; Figure 3). On the other hand, AstraZeneca and Moderna had a comparable RR (1.28, 95% CI: 0.03 to 48.96; Figure 4).   The pooled analysis of three studies showed that the incidence of arrhythmia post-AstraZeneca vaccine was 0.04%, 95% CI: (0.00% to 0.98%). The IRR arrhythmia post-Pfizer or Moderna COVID-19 vaccines was 5.5-times and 19-times higher than the IRR of arrhythmia post-AstraZeneca vaccine. Similarly, the pooled RR showed that the Pfizer vaccine had a non-significantly higher RR compared to AstraZeneca (RR = 1.63, 95% CI: 0.77 to 3.46; Figure 3). On the other hand, AstraZeneca and Moderna had a comparable RR (1.28, 95% CI: 0.03 to 48.96; Figure 4).   The random-effect model showed that the incidence of arrhythmia post-CoronaVac and Sinopharm vaccines was 0.01%, 95% CI: (0.00% to 0.03%) and 0.03%, 95% CI: (0.00% to 18.48%), respectively. Compared to CoronaVac, Pfizer, Moderna, AstraZeneca, and Sinopharm had a higher IRR (22-times, 76-times, 4-times, and 3-times higher), respectively. Likewise, Pfizer, Moderna, and AstraZeneca showed a higher IRR than Sinopharm (7.3-times, 25.3-times, and 1.3-times higher). The head-to-head comparison showed that there was no significant difference between the Pfizer and CoronaVac vaccines in terms of RR of arrhythmia (RR = 1.15, 95% CI: 0.43 to 3.05; Figure 5). textwidth The random-effect model showed that the incidence of arrhythmia post-CoronaVac and Sinopharm vaccines was 0.01%, 95% CI: (0.00% to 0.03%) and 0.03%, 95% CI: (0.00% to 18.48%), respectively. Compared to CoronaVac, Pfizer, Moderna, AstraZeneca, and Sinopharm had a higher IRR (22-times, 76-times, 4-times, and 3-times higher), respectively. Likewise, Pfizer, Moderna, and AstraZeneca showed a higher IRR than Sinopharm (7.3times, 25.3-times, and 1.3-times higher). The head-to-head comparison showed that there was no significant difference between the Pfizer and CoronaVac vaccines in terms of RR of arrhythmia (RR = 1.15, 95% CI: 0.43 to 3.05; Figure 5).

Subgroup Analysis
The subgroup analysis according to the study design, sample size, and study setting is presented in Table 3. People from North America had the highest incidence of cardiac arrhythmia post-Pfizer COVID-19 vaccination at 11.95%, 95% CI: (4.92% to 18.98%), followed by Europe at 0.136%, 95% CI: (0.134% to 0.137%), the Middle East at 0.022%, 95% CI: (0.001% to 0.046%), and Asia at 0.006%, 95% CI: (0% to 0.009%). Studies that included a sample size larger than 2000 individuals reported a much lower incidence of cardiac arrhythmia post-Pfizer vaccine than those who included less than 2000. Regarding the study design, cross-sectional studies reported the highest incidence of cardiac arrhythmias compared to cohort studies, case-series studies, and retrospective studies.

Subgroup Analysis
The subgroup analysis according to the study design, sample size, and study setting is presented in Table 3. People from North America had the highest incidence of cardiac arrhythmia post-Pfizer COVID-19 vaccination at 11.95%, 95% CI: (4.92% to 18.98%), followed by Europe at 0.136%, 95% CI: (0.134% to 0.137%), the Middle East at 0.022%, 95% CI: (0.001% to 0.046%), and Asia at 0.006%, 95% CI: (0% to 0.009%). Studies that included a sample size larger than 2000 individuals reported a much lower incidence of cardiac arrhythmia post-Pfizer vaccine than those who included less than 2000. Regarding the study design, cross-sectional studies reported the highest incidence of cardiac arrhythmias compared to cohort studies, case-series studies, and retrospective studies.

Discussion
The current systematic review and meta-analysis showed that the IR of cardiac arrhythmia post-COVID-19 vaccination is rare and ranges between 1 and 76 per 10,000. mRNA vaccines, including Moderna and Pfizer, were associated with a higher IR of arrhythmia than vector-based vaccines. On the other hand, inactivated vaccines, such as CoronaVac and Sinopharm, showed the lowest IR of arrhythmia. Due to the absence of head-to-head comparison in the majority of the included studies and the non-significant difference in the RR between the studied vaccines, further studies are required to validate these findings. We did not find enough data about the risk of arrhythmia associated with the Johnson & Johnson vaccine to be pooled in one meta-analysis. However, the results of individual studies demonstrated that arrhythmia was one of the largest relative risks associated with COVID- 19 [24]. Our findings were limited by the significant heterogeneity between the included studies. There were several causes for this heterogeneity, including the different population characteristics, study setting, study design, and administered vaccine doses. We found that North American studies had the highest incidence of arrhythmia post-Pfizer vaccine, compared to the Asian or Middle Eastern studies. This finding was consistent with the global reports that showed that the American population is more susceptible to cardiac arrhythmia compared to the European and Asian populations [41]. Moreover, we found that the self-reported incidences of cardiac arrhythmia were much higher than those based on clinician diagnosis.
Regarding  1.94), respectively). Most of these patients were over 60 years old (66.5%). About 55.1% of the patients received the first dose of the vaccine, and 44.9% experienced arrhythmia after the second dose. Almost half of the patients already had hypertension, 16% had diabetes, and 12% had other heart diseases. They concluded that they could not highlight a significant association between cardiac arrhythmia and COVID-19 vaccines; however, arrhythmia is an AESI of concern [39]. According to Wong et al., there was no significant difference between CoronaVac and Pfizer in terms of the IRR of arrhythmia, CAD, or MI [37]. Compared to Moderna, the Pfizer vaccine induced a higher risk of arrhythmia (7.5 per 10,000 persons, 95% CI: 1.9 to 11.5 events) [27].
Although the numbers may not be indicative of the true situation, given that the Pfizer-BioNTech COVID-19 vaccine was the first to receive emergency approval from the US-FDA, and thus a large number of doses have been administered up until the period of analysis, one possible explanation is a shorter interval between the two doses, as shown by Kaur et al. [32]. The Case Series Drug Analysis Print published by Pfizer-BioNTech for their COVID-19 vaccine as of May 28, 2021, reported a total of 2342 cardiac AEs, among which 1098 events were classified as palpitations, 16 events were classified as acute myocardial infarction, 38 events as arrhythmia, 24 events as cardiac failure, 46 events as angina pectoris, 32 events as sinus tachycardia, 63 events as cardiac flutter, 62 events as cardiac arrest, 108 events as atrial fibrillation, and 466 events as tachycardia [42]. The rhythm disorders, as reported by AstraZeneca for their COVID-19 vaccine, included 1763 events of palpitations, 6 events of unstable angina, 8 events of supraventricular tachycardia, 8 events of tachyarrhythmia, 21 events of extrasystoles, 34 events of sinus tachycardia, 43 events of arrhythmia, 78 events of atrial fibrillation, and 622 events of tachycardia [43].
When compared with non-vaccinated patients, the Pfizer vaccine was associated with non-statistically significant lower RR of arrhythmia (RR = 0.89, 95% CI: 0.74 to 1.04), according to Barda et al. They also demonstrated that vaccination against SARA-CoV-2 was associated with substantially lower RR of arrhythmia compared to infected patients, who showed a significantly high RR of arrhythmia (RR = 3.83, 95% CI: 3.07 to 4.95; 166.1 events per 100,000 persons) [40]. This is the first systematic review and meta-analysis that investigate the incidence rate of arrhythmia following COVID-19 vaccines. However, we acknowledge that our study has some limitations, including the small number of included studies, the significant heterogeneity, the inability to conduct a subgroup analysis for all vaccines, and the lack of head-to-head comparison in the majority of the included studies.
In conclusion, the current evidence shows that the IR of cardiac arrhythmia post-COVID-19 vaccination is rare and ranges between 1 and 76 per 10,000. mRNA vaccines, including Moderna and Pfizer, were associated with a higher IR of arrhythmia compared to vector-based vaccines. On the other hand, inactivated vaccines, such as CoronaVac and Sinopharm, showed the lowest IR of arrhythmia. Due to the absence of head-to-head comparison in the majority of the included studies and the non-significant difference in the RR between the studied vaccines, further studies are required to validate these findings.