Association Between Vaccination and Acute Myocardial Infarction and Ischemic Stroke After COVID-19 Infection | Acute Coronary Syndromes | JAMA | JAMA Network
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Table 1.  Baseline Characteristics of Study Population by Vaccination Statusa
Baseline Characteristics of Study Population by Vaccination Statusa
Table 2.  Risk for Cardiovascular Events by Vaccination Status
Risk for Cardiovascular Events by Vaccination Status
1.
Xie  Y, Xu  E, Bowe  B, Al-Aly  Z.  Long-term cardiovascular outcomes of COVID-19.   Nat Med. 2022;28(3):583-590. doi:10.1038/s41591-022-01689-3PubMedGoogle ScholarCrossref
2.
Raman  B, Bluemke  DA, Lüscher  TF, Neubauer  S.  Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus.   Eur Heart J. 2022;43(11):1157-1172. doi:10.1093/eurheartj/ehac031PubMedGoogle ScholarCrossref
3.
Fiolet  T, Kherabi  Y, MacDonald  CJ, Ghosn  J, Peiffer-Smadja  N.  Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: a narrative review.   Clin Microbiol Infect. 2022;28(2):202-221. doi:10.1016/j.cmi.2021.10.005PubMedGoogle ScholarCrossref
4.
Thomas  L, Li  F, Pencina  M.  Using propensity score methods to create target populations in observational clinical research.   JAMA. 2020;323(5):466-467. doi:10.1001/jama.2019.21558PubMedGoogle ScholarCrossref
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    Methodologic Concerns
    Jong-hoon Lee, MD | Science and Research Center, Republic of Korea
    This study has several methodological limitations.

    It did not use a self-controlled case-series (SCCS) design for event-dependent exposures which, because individuals act as their own controls, is thought to provide less biased estimates allowing for exposures whose occurrence or the event influences observation [1]. Instead, Kim et al. used inverse probability of treatment weighting (IPTW) to account for differences between never vaccinated (n=62 727) and fully vaccinated (n=168 310) patients,

    Moreover, its many exclusion criteria led to a sample of 231037 out of 592719 patients, leading to only 31 non-vaccinated and 74 fully vaccinated patients with events. Data calculated using
    smaller statistical samples like in this study often contain significant bias.

    This study is too small to conclude, using this study method, that Covid-19 vaccination is protective against AMI and stroke. Unbiased estimates can be derived only when a self-controlled case series is presented.

    Furthermore, we wonder what the estimates might be with the current 4-dose (2 initial + 2 booster dose) vs the studied 2-dose series.

    Reference

    1. Farrington, C.P., H.J. Whitaker, and M.N. Hocine, Case series analysis for censored, perturbed, or curtailed post-event exposures. Biostatistics, 2008. 10(1): p. 3-16.

    CONFLICT OF INTEREST: None Reported
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    Research Letter
    July 22, 2022

    Association Between Vaccination and Acute Myocardial Infarction and Ischemic Stroke After COVID-19 Infection

    Author Affiliations
    • 1Big Data Department, National Health Insurance Service, Wonju, Korea
    • 2Division of Infectious Diseases, Samsung Medical Center, Seoul, Korea
    • 3Korea Disease Control and Prevention Agency, Cheongju, Korea
    • 4Artificial Intelligence and Big-Data Convergence Center, Gachon University College of Medicine, Incheon, Korea
    JAMA. Published online July 22, 2022. doi:10.1001/jama.2022.12992

    Studies have suggested an increased incidence of acute myocardial infarction (AMI) and ischemic stroke after COVID-19 infection related to an increased risk of thrombosis.1,2 Vaccines against SARS-CoV-2 are effective against COVID-19 and its progression to severe disease.3 However, it is unclear if vaccines also prevent secondary complications. We examined the association between vaccination and AMI and ischemic stroke after COVID-19 infection.

    Methods

    We conducted a retrospective cohort study to compare the incidence of AMI and ischemic stroke after COVID-19 infection between patients who were never vaccinated and those who were fully vaccinated (2 doses of mRNA vaccines or viral vector vaccine) against SARS-CoV-2. The Korean nationwide COVID-19 registry (on infection and vaccination) and the Korean National Health Insurance Service database were used. COVID-19 reporting is mandated, and Korea has universal health care coverage. Adults aged 18 years or older who were diagnosed with COVID-19, including asymptomatic infections, between July 2020 and December 2021 were included. Exclusion criteria included (1) outcome events less than 3 months before COVID-19 diagnosis; (2) reinfection; (3) hospitalization for COVID-19 for 30 or more days and, among vaccinated patients, (4) single dose of vaccine; and (5) COVID-19 diagnosis before or within 7 days after the second vaccination. Patients were observed until March 31, 2022.

    The primary outcome was a composite of hospitalizations for AMI and ischemic stroke that occurred 31 to 120 days after COVID-19 diagnosis; these were identified by the diagnosis codes and relevant imaging (eMethods in the Supplement). The first 30 days were excluded because of the difficulty of differentiating cardiovascular events occurring as complications of COVID-19 vs acute phase treatment. Secondary outcomes included the components of the composite outcome. Inverse probability of treatment weighting (IPTW) was used to control for differences in patient characteristics between the 2 groups,4 with standardized differences used to assess the balance of covariates. Logistic regression was performed for IPTW with full vaccination as an independent variable and age, sex, Charlson Comorbidity Index, hypertension, and insurance type as covariates. A Cox proportional hazards model with IPTW was constructed for the outcome events, with sex, age, comorbidities, previous history of outcome events, and the severity of COVID-19 (need for supplementary oxygen [severe], high-flow nasal cannula or higher respiratory support [critical] vs no respiratory support needed) as covariates. The proportionality assumption was tested (zph tests) and met. SAS Enterprise Guide 7.1 (SAS Institute) was used for statistical analysis. A 2-tailed P < .05 was considered significant. This study was approved by the institutional review board of the Gil Medical Center with a waiver of informed consent.

    Results

    Of 592 719 patients with COVID-19 during the study period, 231 037 patients were included, of whom 62 727 were never vaccinated and 168 310 were fully vaccinated. Patients who were fully vaccinated were older and had more comorbidities (Table 1). In contrast, severe or critical COVID-19 was less common in the fully vaccinated group. The differences in age and comorbidities were reduced after weighting, while the severity of COVID-19 became less balanced. The median follow-up duration starting 30 days after COVID-19 was 90 days in the unvaccinated group and 84 days in the fully vaccinated group.

    The composite outcome occurred in 31 unvaccinated patients and 74 fully vaccinated patients, with an incidence of 6.18 vs 5.49 per 1 000 000 person-days (Table 2). The adjusted risk was significantly lower in the fully vaccinated group (adjusted hazard ratio [aHR], 0.42; 95% CI, 0.29-0.62). The adjusted risk was significantly lower in fully vaccinated patients for both AMI (aHR, 0.48; 95% CI, 0.25-0.94) and ischemic stroke (aHR, 0.40; 95% CI, 0.26-0.63). A lower risk for outcome events in fully vaccinated patients was observed in all subgroups, although some did not reach statistical significance, including those with severe or critical infection (Table 2).

    Discussion

    This study found that full vaccination against COVID-19 was associated with a reduced risk of AMI and ischemic stroke after COVID-19. The findings support vaccination, especially for those with risk factors for cardiovascular diseases. Study limitations include that diagnosis codes for reimbursement were used to capture outcome events. Although the operational definition in this study has been widely used, some diagnostic inaccuracies may exist. Also, there were imbalances in patient characteristics by vaccination status. The decision to be vaccinated is affected by multiple factors that may also be associated with cardiovascular risk. A robust model was applied to mitigate the effect of such imbalances, but the possibility of unobserved bias remains.

    Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.
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    Article Information

    Accepted for Publication: July 12, 2022.

    Published Online: July 22, 2022. doi:10.1001/jama.2022.12992

    Corresponding Author: Jaehun Jung, MD, PhD, Department of Preventive Medicine, Gachon University College of Medicine, 38-13, Dokjeom-ro 3, Incheon, 21565, Republic of Korea (eastside1st@gmail.com).

    Author Contributions: Dr Jung had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Kim and Huh contributed equally to this work.

    Concept and design: Kim, Huh, Jung.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Kim, Huh, Jung.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Kim, Huh, Jung.

    Administrative, technical, or material support: Park, Peck, Jung.

    Supervision: Jung.

    Conflict of Interest Disclosures: Dr Huh reported grants from bioMérieux outside the submitted work. No other disclosures were reported.

    Additional Contributions: We thank Do Tae Kang, MS; Soon-Ae Shin, PhD; Jong-Heon Park, MD, PhD; and Jai Yong Kim, MD, PhD, of the National Health Insurance Service, and Sang Won Lee, PhD, of the Korea Disease Control and Prevention Agency for the development and operation of the COVID-19 convergence big data platform. This study used data from the Korean National Health Insurance Service (NHIS-2022-1-363).

    References
    1.
    Xie  Y, Xu  E, Bowe  B, Al-Aly  Z.  Long-term cardiovascular outcomes of COVID-19.   Nat Med. 2022;28(3):583-590. doi:10.1038/s41591-022-01689-3PubMedGoogle ScholarCrossref
    2.
    Raman  B, Bluemke  DA, Lüscher  TF, Neubauer  S.  Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus.   Eur Heart J. 2022;43(11):1157-1172. doi:10.1093/eurheartj/ehac031PubMedGoogle ScholarCrossref
    3.
    Fiolet  T, Kherabi  Y, MacDonald  CJ, Ghosn  J, Peiffer-Smadja  N.  Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: a narrative review.   Clin Microbiol Infect. 2022;28(2):202-221. doi:10.1016/j.cmi.2021.10.005PubMedGoogle ScholarCrossref
    4.
    Thomas  L, Li  F, Pencina  M.  Using propensity score methods to create target populations in observational clinical research.   JAMA. 2020;323(5):466-467. doi:10.1001/jama.2019.21558PubMedGoogle ScholarCrossref
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