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INTRODUCTION
The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on patients with cancer. In this patient population, the mortality risk associated with COVID-19 infection is significantly elevated, indicating a clear vulnerability to the disease.12 Therefore, it is imperative to prevent COVID-19 infection in this population through vaccination. However, cancer patients have largely been excluded from clinical trials assessing the efficacy of COVID-19 vaccination, resulting in a lack of data on the safety of COVID-19 vaccines for patients with active cancer.3
During the COVID-19 pandemic, large-scale vaccination was conducted worldwidely. COVID-19 vaccination was considered generally safe and effective for the eligible population. However, there have been reports of rare yet severe cardiovascular adverse events occurring following COVID-19 vaccination, such as myocarditis, pericarditis, and cerebral venous thrombosis.4567 A number of studies have raised concerns regarding a possible linkage between COVID-19 vaccination and critical cardiovascular events.8910 However, there is still limited information on adverse cardiovascular events following COVID-19 vaccination, and prior studies mainly focused on the general population. In particular, cancer patients have several conditions that predispose them to cardiovascular complications.11 Therefore, understanding the cardiovascular safety of COVID-19 vaccination for cancer patients, who may be susceptible to both COVID-19-related and cardiovascular complications, is crucial in developing clinical strategies tailored to this specific population.
Various factors could potentially impede the effectiveness of COVID-19 vaccination for cancer patients compared with the general population.12 One such factor is the potential link between COVID-19 vaccination and cardiovascular events. This risk is compounded by fears that COVID-19 vaccination might induce thrombosis, thereby increasing cardiovascular complications. The higher mortality risk of cancer patients who have experienced cardiovascular events such as stroke or myocardial infarction adds to these concerns. The fear of potential cardiovascular risks due to vaccination may hamper COVID-19 prevention efforts in this vulnerable group of patients. Given the heightened mortality and vulnerability in cancer patients, this is a significant concern that could obstruct appropriate vaccination. We aimed to investigate the association between COVID-19 vaccination and cardiovascular events in cancer patients in this study by utilizing nationwide real-world data.
METHODS
Data sources
This study utilized the K-COV-N cohort (Korea Disease Control and Prevention Agency-COVID-19-National Health Insurance Service cohort: KDCA-COVID-19-NHIS cohort), which is a linked dataset of the COVID-19 infection registry, COVID-19 vaccination registry, and NHIS claims data. As South Korea operates a single-payer system through the NHIS, the NHIS database covers the entire population in South Korea and includes information on demographics and healthcare utilization (e.g., diagnoses, procedures, and prescription of medication) from all levels of care. The COVID-19 infection and vaccination registries are managed by the KDCA and include data on COVID-19 infection cases (e.g., infection date) and vaccination cases (e.g., vaccine type, vaccination date, and vaccine dose). In this context, the K-COV-N cohort provides an appropriate setting to investigate the risk of cardiovascular events after COVID-19 vaccination for patients with cancer. Owing to the data provision policy, we used a 25% random sample of the data stratified by age and sex, which included approximately 12 million individuals.
Study design and study population
We adopted a self-controlled case series (SCCS) design, which is a within-person comparison method where each individual serves as their own control. We included patients who had a cancer diagnosis between July 1, 2018 and February 25, 2021 and were aged 12 years or older, which was the recommended age threshold for COVID-19 vaccination during the study period.13 Patients with cancer were identified based on the diagnostic codes (International Classification of Diseases-10th C code), with special identification codes (V027, V193, and V194) applied for financial benefits to cancer patients in South Korea. Among these populations, patients who experienced the cardiovascular events of interest between February 26, 2021 and December 31, 2021 were identified as the final study population. Cardiovascular outcomes of interest were prespecified as myocardial infarction, stroke including ischemic stroke and hemorrhagic stroke, venous thromboembolism (VTE) including deep vein thrombosis (DVT), pulmonary embolism (PE), and cerebral venous sinus thrombosis (CVST), myocarditis, and pericarditis and any of these cardiovascular outcomes. Given that the SCCS design assumes that the occurrence of events should be independent, we considered only incident events for our study as the following cardiovascular events during the observational period are unlikely to be independent. Detailed definitions for the events of interest and cancer diagnosis are presented in Supplementary Table 1.
Exposure
The exposure of interest was the administration of COVID-19 vaccines including BNT162b2, mRNA-1273, ChAdOx1 nCoV-19, and AD26.COV2-S. The risk period was defined as 0–28 days after the first, second, or third dose of the vaccines. We additionally defined the pre-risk period (pre-exposure period) as 21 days before the vaccination because if the patients had occurrence of outcome (cardiovascular events), it may delay the exposure (vaccination). The control period was defined as all other periods within the observational period (excluding risk period and pre-risk period). In cases where the interval between the doses was less than 28 days, the risk period for the corresponding dose ended on the day before the next dose. The observational period started on the first day of the COVID-19 vaccination program, which was February 26, 2021 in South Korea, and ended on December 31, 2021. The SCCS design scheme is presented in Fig. 1.
Statistical analysis
The baseline characteristics of the study population are presented as the mean ± standard deviation (SD) for continuous variables and number (percentage) for categorical variables, which included age, sex, type of cancer (solid tumor and hematologic malignancy), comorbidities (hypertension, diabetes, and atrial fibrillation), and Charlson comorbidity index (CCI). Age and sex were recorded at the start of the observational period, and the comorbidities and CCI of patients were determined within 1 year before the start of the observational period. We also presented the type of vaccine, vaccination dose, and history of COVID-19 infection during the study period.
In each risk period, the incidence rate for individual cardiovascular outcomes was calculated as the number of events per 1,000 person-days. Then, the incidence rate ratios (IRRs) were estimated by comparing the incidence rates of outcomes between the risk and control period. We used a conditional Poisson regression model to estimate the IRR and 95% confidence interval (CI) while adjusting for previous cardiovascular history, COVID-19 infection history and season by 3-month categories (Dec–Feb, Mar–May, Jun–Aug, Sep–Nov). Subgroup analyses were conducted according to the vaccine type (mRNA vaccine, ChAdOx1 nCov-19 vaccine, mix-matched vaccination), age group (< 65 and ≥ 65), gender, and type of cancer (solid tumor and hematologic malignancy). Additionally, we performed sensitivity analysis by excluding individuals who died during the observational period in consideration of the assumption of the SCCS method, i.e., the occurrence of an event should not influence the duration of the observation period. All statistical analyses were performed using SAS Enterprise Guide version 7.1 (SAS Institute, Cary, NC, USA).
RESULTS
Baseline characteristics
Among 12,354,278 individuals aged 12 years or older between July 1, 2018 and December 31, 2021, we identified 318,105 patients diagnosed with cancer, of whom 4,754 patients were diagnosed with cardiovascular outcomes during the study period. Specifically, there were 2,576 cases of VTE, 1,764 cases of stroke, 327 cases of myocardial infarction, 81 cases of myocarditis, and 68 cases of pericarditis (Fig. 2). The baseline characteristics and comorbidities of the study population are summarized in Table 1. The mean ± SD age of individuals with cardiovascular outcomes ranged from 49.9 ± 13.3 years for those with myocarditis to 73.1 ± 11.1 years for those with stroke.
Fig. 2
Flow chart of study population selection.
KDCA = Korea Disease Control and Prevention Agency, NHIS = National Health Insurance Service, VTE = venous thromboembolism, CV = cardiovascular.
Table 1
Baseline characteristics of the study populations
Risk for cardiovascular events
There was no increased risk of overall cardiovascular outcomes after COVID-19 vaccination among patients with cancer (IRR, 0.99; 95% CI, 0.90–1.08). Likewise, no increased risk was observed for myocardial infarction, stroke including ischemic stroke and hemorrhagic stroke, VTE including DVT, PE, and CVST, and pericarditis following COVID-19 vaccination (Table 2, Supplementary Table 2). However, for myocarditis, the adjusted IRR was increased during the whole risk period (IRR, 11.71; 95% CI, 5.88–23.35).
Table 2
Risk of cardiovascular events following coronavirus disease 2019 vaccination among patients with cancer
The results according to the vaccine type are presented in Fig. 3 and Supplementary Table 3. The adjusted IRRs for overall cardiovascular outcomes during the whole risk period for each vaccine type were 1.07 (95% CI, 0.95–1.21) for mRNA vaccines, 0.99 (95% CI, 0.83–1.19) for ChAdOx1 nCoV-19 vaccine, and 0.86 (95% CI, 0.68–1.10) for mix-matched vaccination. Among patients who received mRNA vaccines, elevated risks of myocarditis during the whole risk period and pericarditis during the risk period after the second dose were observed, with adjusted IRRs (95% CIs) of 12.37 (5.58–27.43) and 3.02 (1.22–7.46), respectively. For ChAdOx1 nCoV-19 vaccine recipients, no increased risk of other cardiovascular outcomes except for myocarditis was observed (adjusted IRR, 25.05 [95% CI, 2.93–214.40]). As a considerable number of individuals in South Korea completed their primary series with ChAdOx1 nCoV-19 and later received mRNA vaccines as booster doses, we also investigated mix-matched vaccination and found that there was no increased risk of cardiovascular outcomes in this group.
Subgroup analysis/sensitivity analysis
Subgroup analyses were conducted with stratification by age group, gender, and cancer type. The results were generally consistent with the overall findings. In terms of age, the elderly population aged 65 years or older showed a relatively safe cardiovascular risk profile, whereas higher risks of myocarditis and total cardiovascular outcomes were observed in the younger population (Supplementary Table 4). Subgroup analysis according to gender showed an elevated risk of myocarditis in both males and females (Supplementary Table 5). No significant difference was observed between patients with solid tumors and those with hematologic malignancies (Supplementary Table 6).
In sensitivity analysis excluding individuals who died during the study period, the results were consistent with the main findings (Supplementary Table 7).
DISCUSSION
This study investigated the risk of cardiovascular events associated with administration of the ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273 vaccines, which were primarily used for COVID-19 vaccination in Korea.14 In this large-scale SCCS study based on a nationwide database involving over 318,000 cancer patients, we found no increase in the overall risk of cardiovascular outcomes in cancer patients, except for myocarditis. This finding indicates that COVID-19 vaccination is generally safe for cancer patients in terms of cardiovascular outcomes and provides evidence to support the recommendation of COVID-19 vaccination for cancer patients.
In comparison with the general population, cancer patients present unique considerations regarding COVID-19 vaccination. Major clinical trials for COVID-19 vaccines have shown inadequate evidence relevant to cancer patients. There remain concerns regarding the immunogenicity and efficacy of COVID-19 vaccines in this demographic.1516 Particularly, those with hematological malignancies or recent chemotherapy are more prone to severe COVID-19 trajectories and higher mortality rates, partly due to their immunosuppressed state from malignancies and anticancer treatments.17
During the vaccination campaign, several cardiovascular adverse events such as myocarditis and pericarditis have been reported, and several studies on the risk of cardiovascular complications following COVID-19 vaccination have been proactively carried out. Various studies have reported the relationship between mRNA COVID-19 vaccination and myocarditis and pericarditis.69 The compounded effect of myocardial damage induced by both COVID-19 and anticancer drugs can further escalate the occurrence of cardiovascular adverse outcomes. Moreover, apprehension of vascular events can induce fear of COVID-19 vaccination. Notably, cancer patients have an increased incidence of cardiovascular events, including venous thromboembolic events. Thromboembolic events, common complications in cancer patients, pose a potentially fatal threat and adversely affect prognosis. Additionally, cardiovascular diseases are a significant cause of mortality among cancer survivors. Thromboembolism associated with cancer is accompanied by a high risk of recurrent thrombosis, bleeding, and early mortality. Moreover, the occurrence of a cardiovascular event can negatively affect the long-term frailty, physical and psychological functions, and overall quality of life of cancer patients. Together, these factors can potentially contribute to hesitancy towards COVID-19 vaccination among cancer patients.
In contrast to the general population, cancer patients have a higher risk of severe COVID-19 complications or mortality. Current guidelines are typically predicated on the assumption that the benefits of COVID-19 vaccination for cancer patients outweigh the risks; however, the clinical evidence supporting this stance is insufficient.18 Consequently, there is a pressing need for studies on cardiovascular events following COVID-19 vaccination in cancer patients. Post-COVID-19 sequelae affect up to 15% of patients with cancer and have adverse effects on both survival and oncological outcomes after recovery.19 Myocardial damage induced by both COVID-19 and anticancer drugs might synergistically contribute to an increase in cardiovascular adverse events, as described by the “two-hit” model.20 Among patients with both cancer and COVID-19 in a previous study, the 30-day all-cause mortality rate was high, influenced by both general risk factors and cancer-specific risk factors.17 Due to their systemic immunosuppressive state from malignancies and anticancer treatments, patients with cancer are more susceptible than those without cancer to infection, potentially increasing the risk of COVID-19 and a poorer prognosis.21
In our study, both integrated analysis and vaccine type-specific analyses revealed increased risks of myocarditis and pericarditis following COVID-19 vaccination. These results are in agreement with those of previous studies, which reported increased risks of myocarditis and pericarditis after COVID-19 vaccination in the general population. Therefore, it is essential to remain vigilant and consider the risk of myocarditis and pericarditis when administering COVID-19 vaccines to cancer patients. Nevertheless, it is imperative to note that multiple preceding studies have consistently reported a much higher risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in unvaccinated populations. Therefore, despite the increased cardiovascular risk, it is crucial to acknowledge that COVID-19 vaccination may be considered a justified and beneficial measure to protect against the disease.1822
An increased risk of myocarditis has been predominantly reported in young men who received mRNA-type COVID-19 vaccines.6923 However, a marked increase in the risk of myocarditis was also observed in the ChAdOx nCoV-19 recipients and female subgroup in our study. Several studies and case reports have reported the risk and occurrence of myocarditis after COVID-19 vaccination not only among mRNA vaccine recipients but also among ChAdOx nCoV-19 recipients. Moreover, an increased risk of myocarditis following COVID-19 vaccination in the female population has been reported.2425 Although further research is required, it is necessary to be aware of the risk of myocarditis irrespective of the vaccine type or gender when considering COVID-19 vaccination for patients with cancer.
In previous safety studies on COVID-19 vaccines for cancer patients, these vaccines have generally been deemed safe; however, the evidence on cardiovascular adverse events is limited. Due to the weaker immune response to COVID-19 vaccines in cancer patients, there is a greater need for additional booster shots. Consequently, it is imperative to be more vigilant towards the risk of vaccine-related adverse events in this population.
The SCCS method was originally developed to estimate the relative risk of an acute event in a pre-defined risk period compared with the control period. It is widely utilized as a method for vaccine safety studies as this approach allows comparisons within individual to exclude time-invariant confounding factors.2627 In this regard, our study also implemented the SCCS design to evaluate cardiovascular risk after COVID-19 vaccination.
Despite the lack of data on cancer patients during the clinical development of COVID-19 vaccines, the administration of COVID-19 vaccines for cancer patients was crucial to mitigate the spread of this infectious disease during the pandemic. Even as the pandemic wanes, the SARS-CoV-2 virus continues to evolve into various variants of concern. Particularly, in high-risk populations such as patients with cancer are expected to be persistently recommended for COVID-19 vaccination. A strength of our study is that we provided evidence and future landscape regarding the safety of COVID-19 vaccination in a cancer population utilizing an extensive real-world vaccination data collected during the pandemic period.
Several limitations in our study should be noted. Due to the restricted availability of data at the time of data provision, it was not possible to include the data on the safety of the fourth (or more) booster dose or novel types of protein subunit vaccines, which were approved much later. A comparison with the cardiovascular risk of unvaccinated individuals with SARS-CoV-2 infection was not performed. Additionally, as our database does not contain detailed clinical information such as the stage of cancer, we defined the cancer patients using the diagnostic codes and specific identification codes. Although the specific identification codes would have high specificity in identifying the cancer patients, future studies with clinical information including stage of cancer would be informative to establish detailed recommendations among these patients.
The findings of this study may be considered as supportive of COVID-19 vaccination for cancer patients. Although an increased risk of myocarditis following COVID-19 vaccination was observed in cancer patients, it is noteworthy that it was comparatively safe in terms of other overall cardiovascular risks. This study contributes to the field by providing evidence on cardiovascular risk associated with COVID-19 vaccination for patients with cancer.
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